Pancreatic Ductal Adenocarcinoma

MONDO:0005184 Pathograph 32 Show in embeddings browser pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer, accounting for approximately 90% of pancreatic malignancies. It is characterized by near-universal KRAS oncogene mutations (~90%), frequent inactivation of tumor suppressors TP53, SMAD4, and CDKN2A, and a dense desmoplastic stroma that contributes to treatment resistance and immune evasion. PDAC has one of the worst prognoses of any solid tumor with a 5-year survival rate of approximately 12%. Standard treatments include surgical resection (Whipple procedure) for the minority with resectable disease, and gemcitabine-based or FOLFIRINOX chemotherapy regimens.

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Classifications

ICD-O Morphology

Harrison's Part

🔗

Mappings

MONDO

MONDO:0005184 pancreatic ductal adenocarcinoma

MONDO provides an exact disease term for pancreatic ductal adenocarcinoma.

NCIT

NCIT:C9120 Pancreatic Ductal Adenocarcinoma

NCIT provides an exact neoplasm term for pancreatic ductal adenocarcinoma.

ICD-10-CM

ICD10CM:C25.3 Malignant neoplasm of pancreatic duct

ICD-10-CM provides an exact malignant neoplasm code for pancreatic duct.

NCIT

NCIT:C9120 Pancreatic Ductal Adenocarcinoma

NCIT provides an exact neoplasm term for pancreatic ductal adenocarcinoma.

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Subtypes

Classical Subtype

Characterized by expression of epithelial differentiation genes and transcription factors such as GATA6. Generally associated with better prognosis compared to basal-like subtype.

Show evidence (1 reference)

PMID:26343385 SUPPORT Computational

"we have identified and validated two tumor subtypes, including a 'basal-like' subtype that has worse outcome and is molecularly similar to basal tumors in bladder and breast cancers."

Moffitt et al. used virtual microdissection of gene expression data to identify classical and basal-like subtypes of PDAC, with classical having better prognosis.

Basal-like Subtype

Characterized by expression of basal/squamous markers and loss of GATA6. Associated with worse prognosis, higher metastatic potential, and resistance to chemotherapy.

Show evidence (1 reference)

PMID:26343385 SUPPORT Computational

"patients with basal-like subtype tumors had an overall worse median survival of 11 months and 44% 1-year survival compared to 19 months and 70% 1-year survival for those with classical subtype tumors"

Moffitt et al. demonstrated basal-like subtype has significantly worse survival compared to classical subtype in PDAC.

Comorbidities

Chronic Pancreatitis <-> Pancreatic Ductal Adenocarcinoma

Discussions and Knowledge Gaps

Which cancer-associated fibroblast programs actively cause T-cell exclusion and checkpoint resistance in PDAC, and which stromal programs are tumor-restraining or merely correlative with desmoplastic burden?

KNOWLEDGE GAP OPEN gap_pdac_caf_program_t_cell_exclusion

Attached to

pathophysiology#Desmoplastic Stroma pathophysiology#CAF-Mediated T Cell Exclusion pathophysiology#Immune Evasion

PDAC desmoplasia is not a single therapeutic target: some CAF states may exclude effector T cells, whereas others may restrain invasion. A patient-derived organ-on-chip experiment can test whether specific CAF programs are causal for immune exclusion and whether reprogramming them improves T-cell cytotoxicity without removing tumor-restraining stroma.

Proposed experiments

Patient-derived PDAC organ-on-chip CAF reprogramming and T-cell infiltration assay

patient-derived organ-on-chip immunotherapy perturbation experiment

exp_pdac_patient_ooc_caf_t_cell_exclusion

Assemble a patient-derived PDAC organoid organ-on-chip with fibroblasts, endothelium, and immune cells; induce or suppress CAF programs including interferon-response CAF states; then measure T-cell infiltration, cytotoxicity, tumor viability, and stromal remodeling under checkpoint blockade.

Model systems

Patient-derived PDAC tumor-microenvironment organ-on-chip

Microfluidic human PDAC model combining patient-derived tumor organoids with fibroblasts, endothelial cells, and immune cells so stromal crosstalk, T-cell migration, and drug response can be measured in a standardized ex vivo platform.

ORGAN ON CHIP namo:OrganOnChip link

human NCBITaxon:9606

pancreas UBERON:0001264

pancreatic ductal cell CL:0002079 fibroblast CL:0000057 endothelial cell CL:0000115 T cell CL:0000084

Perturbations

CAF subtype induction and depletion

pathophysiology#Desmoplastic Stroma

Induce, suppress, or selectively deplete CAF states to separate immune-excluding and tumor-restraining stromal programs.

FAP

extracellular matrix organization GO:0030198

STING-driven interferon-response CAF induction

pathophysiology#CAF-Mediated T Cell Exclusion

STING agonism or matched interferon-response induction used to test whether an interferon-response CAF state decreases invasion and improves antitumor immune activity.

type I interferon signaling pathway GO:0060337

Immune checkpoint blockade

pathophysiology#Immune Evasion

Anti-PD-1/PD-L1 or matched checkpoint blockade applied with CAF perturbation to test whether stromal reprogramming is required for T-cell cytotoxicity.

immunotherapy NCIT:C15262

Readouts

T-cell infiltration and cytotoxicity

pathophysiology#CAF-Mediated T Cell Exclusion

Spatial T-cell entry into tumor organoid regions, activation markers, and tumor-cell killing after CAF-state perturbation.

T cell activation GO:0042110

high-content live imaging cytotoxicity assay

Direction: NEGATIVE

CAF-state trajectory

pathophysiology#Desmoplastic Stroma

Single-cell and spatial profiling of inflammatory, myofibroblastic, and interferon-response CAF programs after stromal perturbation.

single-cell transcriptomic profiling spatial transcriptomic profiling

Direction: POSITIVE

Tumor organoid viability under checkpoint blockade

pathophysiology#Immune Evasion

Tumor-cell survival after combined CAF perturbation and checkpoint blockade.

cell viability assay

Direction: NEGATIVE

Controls

Tumor organoid without CAF compartment

Patient-derived PDAC organoid chip lacking fibroblasts.

CAF-intact chip without T cells

Stromal chip lacking effector T cells to distinguish direct stromal effects from immune-mediated killing.

Isotype-control checkpoint antibody

Matched antibody control for checkpoint blockade.

Decision criterion

A causal CAF immune-exclusion program is supported if its induction reduces T-cell entry or killing and its suppression restores checkpoint response. A tumor-restraining CAF state is supported if induction lowers invasion or viability while preserving or improving T-cell function.

Would support

pathophysiology#CAF-Mediated T Cell Exclusion pathophysiology#Immune Evasion

Would refute

pathophysiology#CAF-Mediated T Cell Exclusion

Show evidence (3 references)

PMID:41610338 SUPPORT In Vitro

"incorporating PDOs with key components of the TME (fibroblasts, endothelial cells, and immune cells) within a microfluidic system"

Provides the recent patient-derived organ-on-chip precedent for a PDAC tumor-microenvironment experiment with stromal and immune compartments.

PMID:41610338 SUPPORT In Vitro

"model and assess the efficacy of immune checkpoint blockade for T cell cytotoxicity in PDAC"

Supports using this platform to adjudicate checkpoint response in the presence of patient-derived stromal context.

+ 1 more reference

⚙

Pathophysiology

Chronic Pancreatic Inflammation

Sustained inflammatory injury of the exocrine pancreas, the non-genetic half of PDAC initiation. Oncogenic KRAS on its own is not sufficient in the adult pancreas: the same allele that drives disease when expressed embryonically leaves adult mice refractory until the tissue is inflamed, at which point the full PanIN-to-carcinoma sequence follows. This node is what the entry's environmental exposures actually act on, and it is the substrate on which mutant KRAS becomes tumorigenic.

macrophage CL:0000235 pancreatic stellate cell CL:0002410

inflammatory response GO:0006954 ↑ INCREASED

pancreas UBERON:0001264

Downstream

Acinar-to-Ductal Metaplasia Inflammatory injury drives acinar cells out of their differentiated state and into a ductal-like phenotype, which is the metaplastic response this node's target models.

Show evidence (2 references)

PMID:17349585 SUPPORT Model Organism

"These observations suggest that, during adulthood, PDA stems from a combination of genetic (e.g., somatic K-Ras mutations) and nongenetic (e.g., tissue damage) events."

States the two-component model directly: the genetic lesion is modeled by the KRAS node and the nongenetic tissue-damage component is what this node is for.

PMID:35142721 SUPPORT Human Clinical

"There is an increased risk of PDAC in patients with CP, and incidence rates increase with CP disease duration."

The human counterpart of the mouse result, with risk rising as the inflammation persists. PARTIAL because it measures cancer incidence in inflamed pancreata rather than anything at this node itself.

Acinar-to-Ductal Metaplasia

Differentiated acinar cells transdifferentiate into ductal-like cells. This is the predominant form of pancreatic ductal metaplasia and the cellular state in which PanIN lesions arise, which places the origin of PDAC in the acinar compartment rather than in pre-existing ducts despite the tumour's ductal histology.

pancreatic acinar cell CL:0002064 pancreatic ductal cell CL:0002079

transdifferentiation GO:0060290 ↑ INCREASED

Downstream

Tumor Suppressor Inactivation Metaplastic ducts give rise to PanIN lesions, which accumulate CDKN2A, TP53 and SMAD4 loss as they progress from low to high grade. The PanIN stage itself is the known intervening step and is not a separate node in this entry.

Show evidence (2 references)

PMID:35176433 SUPPORT Other

"Acinar to ductal metaplasia (ADM) is the predominant form of ductal metaplasia in pancreas."

Establishes ADM as the dominant metaplastic route in this organ, which is what this node models.

PMID:17349585 SUPPORT Model Organism

"suggesting that PDA originates by differentiation of acinar/centroacinar cells or their precursors into ductal-like cells"

Lineage evidence that the ductal-like cells of PDAC descend from the acinar compartment, which is the transdifferentiation this node annotates.

KRAS Oncogene Activation

Activating mutations in KRAS (predominantly G12D, G12V, G12R) occur in approximately 90% of PDAC and are considered the initiating oncogenic event. Mutant KRAS is constitutively GTP-bound, driving aberrant activation of RAF-MEK-ERK and PI3K-AKT-mTOR signaling cascades that promote cell proliferation, survival, and metabolic reprogramming.

pancreatic ductal cell CL:0002079

MAPK cascade GO:0000165 ↑ INCREASED phosphatidylinositol 3-kinase signaling GO:0043491 ↑ INCREASED cell population proliferation GO:0008283 ↑ INCREASED

Downstream

Immunosuppressive TME Reversibility under RAS(ON) Inhibition Because the immunosuppressive microenvironment is maintained by oncogenic KRAS signalling, inhibiting it reverses the myeloid and T-cell programs curated on the nodes downstream of this one.

Acquired RAS(ON) Inhibitor Resistance The same KRAS dependence that RAS(ON) multiselective inhibitors exploit is the node on which the acquired-resistance mechanisms curated here converge.

Early Dissemination and EMT The initiating KRAS lesion also licenses the cellular plasticity and EMT-like transitions through which PDAC cells disseminate before the primary tumour becomes clinically dominant.

Acinar-to-Ductal Metaplasia Mutant KRAS expressed in the acinar/centroacinar lineage drives those cells into the ductal-like state, so the metaplasia node is downstream of the oncogene as well as of the inflammation. Both inputs are required in the adult pancreas.

Tumor Suppressor Inactivation KRAS activation cooperates with loss of tumor suppressors for full malignant transformation

Show evidence (3 references)

PMID:35302596 SUPPORT Other

"KRAS mutation (MT) is a major oncogenic driver in pancreatic ductal adenocarcinoma (PDAC)."

This directly supports KRAS as the central driver pathway in PDAC.

DOI:10.3389/fmed.2024.1369136 SUPPORT Human Clinical

"In the case of pancreatic ductal adenocarcinomas (PDAC), 90-92% harbor mutations in the oncogene KRAS, triggering canonical MAPK signaling."

This review confirms that 90-92% of PDAC harbor KRAS mutations that trigger canonical MAPK signaling, supporting the central role of KRAS in PDAC pathogenesis.

DOI:10.1093/carcin/bgae064 SUPPORT Human Clinical

"PanIN development begins with Kirsten rat sarcoma viral oncogene (KRAS) mutations driving PanIN initiation. Key additional mutations in cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor protein p53 (TP53), and mothers against decapentaplegic homolog 4 (SMAD4) disrupt cell cycle control and..."

This review confirms KRAS mutations as the initiating event in PanIN development, with additional tumor suppressor losses driving progression to invasive carcinoma.

Tumor Suppressor Inactivation

Progressive inactivation of key tumor suppressors drives PDAC progression. TP53 mutations (~75%) disable DNA damage checkpoints and apoptosis. CDKN2A loss (~90%) removes cell cycle inhibition via p16INK4a. SMAD4 inactivation (~55%) disrupts TGF-beta tumor-suppressive signaling. These losses cooperate with KRAS activation to enable genomic instability and malignant transformation.

regulation of cell cycle GO:0051726 ⚠ ABNORMAL apoptotic process GO:0006915 ↓ DECREASED DNA damage response GO:0006974 ⚠ ABNORMAL

Downstream

Desmoplastic Stroma Genomic instability and tumor-stroma crosstalk promote desmoplasia

Extracellular Vesicle-Mediated Immune Escape Transformed PDAC cells release functionally active exosomes that condition host tissue ahead of metastasis

Show evidence (1 reference)

PMID:18772397 SUPPORT Human Clinical

"This list includes the classic tumor suppressor genes CDKN2A (p16), SMAD4, and TP53, as well as genes that had not previously been implicated in pancreatic cancer development."

The landmark Jones et al. genomic analysis identified CDKN2A, SMAD4, and TP53 as core tumor suppressor genes in pancreatic cancer through global sequencing of 24 advanced pancreatic adenocarcinomas.

Desmoplastic Stroma

PDAC is characterized by a dense desmoplastic stroma comprising up to 80% of tumor mass. Pancreatic stellate cells (PSCs) are activated by tumor-derived signals (TGF-beta, PDGF, sonic hedgehog) and differentiate into myofibroblasts that deposit abundant extracellular matrix including collagen and hyaluronan. This stroma creates high interstitial pressure, impairs drug delivery, promotes immune exclusion, and provides survival signals to tumor cells.

pancreatic stellate cell CL:0002410

extracellular matrix organization GO:0030198 ↑ INCREASED collagen biosynthetic process GO:0032964 ↑ INCREASED

Computational models

PDAC CAF-Mediated Invasion PhysiCell Model AGENT BASED PhysiCell Implements ECM-driven fibroblast motility and epithelial-mesenchymal state switching encoded in `config/cell_rules.csv` for the stromal invasion program.

Downstream

CAF-Mediated T Cell Exclusion Activated fibroblast states and ECM-rich niches spatially exclude effector T cells and reinforce immune suppression

Show evidence (2 references)

DOI:10.3390/cancers16162876 SUPPORT Human Clinical

"Cells of the tumor microenvironment (TME) interact with cancer cells in pancreatic ductal adenocarcinoma (PDAC) tumors to preserve cancer cells' metabolism, inhibit drug delivery, enhance immune suppression mechanisms and finally develop resistance to chemotherapy and immunotherapy."

This review confirms that the PDAC TME inhibits drug delivery and enhances immune suppression, consistent with the role of the desmoplastic stroma in treatment resistance.

DOI:10.1146/annurev-pathmechdis-031621-024600 SUPPORT Human Clinical

"Pancreatic ductal adenocarcinoma (PDAC) features a prominent stromal microenvironment with remarkable cellular and spatial heterogeneity that meaningfully impacts disease biology and treatment resistance."

This review describes the prominent stromal microenvironment in PDAC and its role in treatment resistance, supporting the desmoplastic stroma mechanism.

CAF-Mediated T Cell Exclusion

Distinct cancer-associated fibroblast states within PDAC stroma secrete extracellular matrix and chemokine programs that trap or exclude effector T cells from tumor nests. This stromal immune exclusion helps explain the poor activity of checkpoint blockade in unselected PDAC and is a natural mechanistic bridge between desmoplasia and immune escape.

pancreatic stellate cell CL:0002410 CD8-positive, alpha-beta T cell CL:0000625

chemokine-mediated signaling pathway GO:0070098 ↑ INCREASED Negative Regulation of T Cell Mediated Immunity GO:0002710 ↑ INCREASED

Downstream

Immune Evasion Stromal chemokines and fibroblast-rich exclusion zones reduce effective anti-tumor T cell contact with malignant glands

Extracellular Vesicle-Mediated Immune Escape

PDAC tumor cells secrete extracellular vesicles (exosomes and microvesicles) carrying immunomodulatory molecules and tumor-associated signals. The experimentally resolved arm of this mechanism is myeloid: PDAC-derived exosomes are taken up by resident tissue macrophages (Kupffer cells), which respond by secreting TGF-beta and establishing a fibrotic microenvironment that recruits further bone marrow-derived macrophages. The exosomal cargo protein macrophage migration inhibitory factor (MIF) is required for this reprogramming — blocking it prevents niche formation and metastasis — identifying EV cargo transfer as a causal, not merely correlative, route by which PDAC conditions host tissue in favor of tumor progression.

pancreatic ductal cell CL:0002079 Kupffer cell CL:0000091 recruited bone marrow-derived macrophage CL:0000235

extracellular exosome biogenesis GO:0097734 ↑ INCREASED transforming growth factor beta production GO:0071604 ↑ INCREASED

Downstream

Immune Evasion EV-delivered cargo reprograms resident and recruited macrophages toward the immunosuppressive myeloid compartment that characterizes the PDAC microenvironment

Show evidence (3 references)

PMID:25985394 SUPPORT Model Organism

"Uptake of PDAC-derived exosomes by Kupffer cells caused transforming growth factor β secretion and upregulation of fibronectin production by hepatic stellate cells. This fibrotic microenvironment enhanced recruitment of bone marrow-derived macrophages."

Primary experimental evidence that PDAC-derived exosomes are taken up by resident macrophages and reprogram them, supporting the macrophage cell-type annotation and the TGF-beta production process on this node.

PMID:25985394 SUPPORT Model Organism

"We found that macrophage migration inhibitory factor (MIF) was highly expressed in PDAC-derived exosomes, and its blockade prevented liver pre-metastatic niche formation and metastasis."

Loss-of-function evidence that a specific exosomal cargo protein is causally required, establishing EV cargo transfer rather than mere EV presence as the operative mechanism.

PPR:PPR1285314 Preprint · not peer-reviewed SUPPORT Computational

"Tumour-derived extracellular vesicles (EVs) contribute to PDAC progression by transferring immunomodulatory molecules and tumour-associated signals, suggesting EV-associated processes as potential intervention opportunities."

Cited only for the general framing that tumor-derived EVs transfer immunomodulatory cargo in PDAC. This is the preprint's background statement, not its finding — its own contribution is computational candidate prioritization — so it is retained as corroborating context alongside, not in place of, the primary evidence above.

Immune Evasion

PDAC creates a profoundly immunosuppressive tumor microenvironment. The desmoplastic stroma physically excludes cytotoxic T cells. Regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages accumulate and suppress anti-tumor immunity. PDAC tumors also exhibit low mutational burden and poor neoantigen presentation, contributing to resistance to immunotherapy.

regulatory T cell CL:0000815 tumor-associated macrophage CL:0000235

immune response GO:0006955 ↓ DECREASED

Computational models

PDAC Immunotherapy PhysiCell Model AGENT BASED PhysiCell Encodes PD-L1-dependent suppression of T-cell motility and attack probabilities, plus macrophage inflammatory-state rules, in `config/cell_rules.csv`.

Show evidence (2 references)

DOI:10.1186/s12943-023-01813-y SUPPORT Human Clinical

"Immunosuppression is a hallmark of pancreatic ductal adenocarcinoma (PDAC), contributing to early metastasis and poor patient survival."

This review establishes immunosuppression as a hallmark of PDAC that contributes to metastasis and poor survival, supporting the immune evasion mechanism.

DOI:10.1186/s12943-023-01813-y SUPPORT Human Clinical

"Following chemokine and exosomal guidance, these cells metastasize to the organ-specific pre-metastatic niches (PMNs) constituted by local resident cells, stromal fibroblasts, and suppressive immune cells, such as the metastasis-associated macrophages, neutrophils, and myeloid-derived suppressor cells."

This describes the immune cell populations in PDAC metastatic niches including macrophages, neutrophils, and MDSCs that constitute the immunosuppressive microenvironment.

Early Dissemination and EMT

Metastatic spread can begin early, before the primary tumor becomes clinically dominant. Cellular plasticity, EMT-like transitions, and squamous or mesenchymal programs enable escape from precursor and invasive lesions.

epithelial to mesenchymal transition GO:0001837 ↑ INCREASED cell migration GO:0016477 ↑ INCREASED

Downstream

Perineural Invasion Invasive, plastic tumour cells track along intrapancreatic nerves, using neural routes as low-resistance conduits for local and regional spread.

Show evidence (1 reference)

PMID:41814069 SUPPORT Other

"We explore the biological and spatial-temporal evolution of precancerous lesions, such as PanINs and IPMNs, and examine how phenotypic plasticity and overlapping cellular programs-including squamous transdifferentiation, epithelial-to-mesenchymal transition (EMT), and acquisition of mesenchymal..."

This directly supports EMT-linked early dissemination in pancreatic adenocarcinoma.

Perineural Invasion

Pancreatic adenocarcinoma has marked neurotropism. Tumor cells track along nerves, exploit neurotrophic cues, and use neural routes as low-resistance corridors for local spread and distant metastatic behavior.

positive regulation of cell migration GO:0030335 ↑ INCREASED

Show evidence (1 reference)

PMID:35449152 SUPPORT Human Clinical

"Perineural invasion (PNI) is a pathologic feature of pancreatic cancer and is associated with poor outcomes, metastasis, and recurrence in pancreatic cancer patients."

This supports perineural invasion as a metastasis-associated feature of pancreatic cancer.

Cyclophilin A Loss and Reduced Tri-Complex Engagement

Under daraxonrasib (RMC-6236) pressure, downregulation of cyclophilin A (PPIA) - the intracellular chaperone the drug must bind to assemble the RAS(ON)-engaging tri-complex - reduces on-target drug engagement while RAS-GTP signaling is retained. This is a drug-class-specific, KRAS-G12D-associated route of acquired resistance to tri-complex RAS(ON) inhibitors.

ras on inhibitor acquired resistance

PPIA hgnc:9253

peptidyl-prolyl cis-trans isomerase activity GO:0003755 ↓ DECREASED

Downstream

Acquired RAS(ON) Inhibitor Resistance Reduced tri-complex engagement lets RAS-GTP signaling and proliferation resume despite continued dosing.

Show evidence (1 reference)

PMID:42465401 SUPPORT In Vitro

"In contrast, KRAS G12D resistance arose through retained KRAS G12D -GTP signaling, with a decrease of cyclophilin A (CypA) protein, the binding partner required for daraxonrasib activity."

Identifies CypA (PPIA) downregulation as a daraxonrasib-specific resistance route in KRAS-G12D PDAC, reducing tri-complex formation while RAS-GTP signaling persists.

RAS-Independent Cell-Cycle Uncoupling

A RAS-independent escape in which cell-cycle progression becomes uncoupled from RAS-MAPK output, so tumor cells continue proliferating despite multiselective RAS(ON) inhibition. Co-targeting the cell-cycle kinases CDK4/6 and CDK2 restores sensitivity; this transcriptional/cell-cycle class of resistance is not reversed by deeper RAS inhibition alone.

ras on inhibitor acquired resistance

cell population proliferation GO:0008283 ↑ INCREASED

Downstream

Acquired RAS(ON) Inhibitor Resistance Proliferation decoupled from RAS sustains tumor growth under continued RAS(ON) inhibition.

Show evidence (1 reference)

PMID:41959066 SUPPORT Model Organism

"While these pathways can be broadly inhibited using the pan-RAS-ON inhibitor RMC-6236, cells remained capable of developing acquired resistance where cell proliferation is uncoupled from RAS signaling."

Establishes RAS-independent cell-cycle continuation under daraxonrasib (RMC-6236) as a resistance route restorable by CDK4/6 and CDK2 co-targeting.

Acquired RAS(ON) Inhibitor Resistance

Convergent outcome node: tumor regrowth under daraxonrasib after an initial response, reflected clinically in the finite progression-free survival observed in RASolute 302. Multiple upstream routes converge here - cyclophilin A loss, RAS-independent cell-cycle uncoupling, RTK/feedback and on-target RAS reactivation, and mTOR/JUN-AP1 hyperactivation; which route dominates in patients is unresolved (no longitudinal daraxonrasib resistance dataset yet).

Show evidence (1 reference)

PMID:42223072 SUPPORT Human Clinical

"The median progression-free survival in the RAS G12 population was 7.3 months with daraxonrasib and 3.5 months with chemotherapy, and that in the overall population was 7.2 months and 3.6 months, respectively; the hazard ratios were 0.45 and 0.49, respectively (P<0.001 for both comparisons)."

The finite progression-free survival on daraxonrasib is the clinical readout of the acquired resistance that the upstream routes converge on.

On-Target RAS Reactivation and KRAS Amplification

Restoration of RAS-GTP above the inhibition threshold via KRAS amplification or a secondary/second-site RAS mutation. Because multiselective RAS(ON) inhibitors suppress mutant and wild-type RAS, many such routes often remain targetable by deeper engagement, so amplification must raise the threshold substantially to drive durable escape.

ras on inhibitor acquired resistance

Downstream

Acquired RAS(ON) Inhibitor Resistance Raised RAS-GTP restores mitogenic signaling despite continued dosing.

Show evidence (1 reference)

PMID:41165456 SUPPORT Model Organism

"Two models reactivated RAS signaling, either via KRASG12C gene amplification or NRASG13R mutation, and were vulnerable to dual inhibition by RAS(ON) G12C-selective and RAS(ON) multiselective inhibitors, RMC-4998 and RMC-7977."

Supported in NSCLC models (tool analog RMC-7977) and inferred for PDAC/daraxonrasib; PARTIAL because these RAS-reactivating routes often remained sensitive to multiselective RAS(ON) inhibition.

RTK and Feedback Pathway Reactivation

Relief of ERK-mediated negative feedback reactivates receptor tyrosine kinases and adaptors (EGFR/ERBB, AXL/PDGFR, SHP2, FAK, YAP-SDC1), restoring RAS-GTP/ERK output or providing RAS-parallel survival signaling. Best demonstrated against partial (MEK/G12C) blockade; its sufficiency against complete RAS(ON) suppression is uncertain.

ras on inhibitor acquired resistance

Downstream

Acquired RAS(ON) Inhibitor Resistance RTK-driven signaling restores proliferation or parallel survival under inhibition.

Show evidence (1 reference)

PMID:41165456 SUPPORT Model Organism

"Two models, which lacked any discernable genomic alteration, acquired resistance associated with increased receptor tyrosine kinase activity and downstream persistent RAS activity and were sensitive to RAS-GTP inhibition by RMC-7977."

RTK-driven persistent RAS activity mediated G12C-inhibitor resistance but remained sensitive to multiselective RAS(ON) inhibition; PARTIAL and context is NSCLC, so sufficiency against complete RAS(ON) block in PDAC is an open question.

Adaptive mTOR and JUN-AP1 Transcriptional Program

Convergent adaptive-transcriptional escape in which mTOR and JUN/AP-1 hyperactivation overcome MAPK suppression; JUN is the most downstream mediator and is indirectly targetable via MAP2K4 inhibition.

ras on inhibitor acquired resistance

Downstream

Acquired RAS(ON) Inhibitor Resistance mTOR/JUN-AP1 output restores proliferation independent of restored RAS-GTP.

Show evidence (1 reference)

PMID:41572361 SUPPORT Model Organism

"Through unbiased CRISPR-based screenings, we identified mTOR and JUN hyperactivation as interconnected mechanisms that overcome MAPK suppression."

PDAC CRISPR screens (explicitly anticipating RAS(ON) multi-selective inhibitor resistance) identify the mTOR/JUN-AP1 hub as an adaptive transcriptional escape.

Mitochondrial Remodeling and Ferroptosis Vulnerability

Profound RAS-MAPK suppression drives persistent mitochondrial remodeling and a lipid-peroxidase/ROS dependency, creating a subtype-independent ferroptosis (GPX4) vulnerability in the resistant state - a salvage target rather than a growth-restoring route.

ras on inhibitor acquired resistance

ferroptosis GO:0097707 ↑ INCREASED

Downstream

Acquired RAS(ON) Inhibitor Resistance The mitochondrial-remodeled state accompanies therapy resistance and defines a ferroptosis salvage vulnerability.

Show evidence (1 reference)

PMID:41545339 SUPPORT Model Organism

"We found that dual SHP2/mitogen-activated protein kinase kinase (MEK1/2) inhibition induces major alterations in mitochondrial mass and function, impacts reactive oxygen species (ROS) homeostasis and triggers lipid peroxidase dependency."

Vertical/direct RAS-pathway inhibition in PDAC induces a persistent mitochondrial-remodeled, ferroptosis-vulnerable resistant state - an actionable metabolic dependency of the resistant tumor.

MYC Amplification-Driven RAS-Independent Proliferation

Amplification of the downstream transcriptional effector MYC is proposed to restore proliferation independent of RAS engagement, a RAS-independent route not reversed by deeper RAS inhibition. Evidence is currently review-level and needs primary, drug-matched confirmation.

ras on inhibitor acquired resistance

Downstream

Acquired RAS(ON) Inhibitor Resistance MYC-driven proliferation bypasses RAS dependence.

Show evidence (1 reference)

PMID:39586491 SUPPORT Other

"MYC amplification was reported to be a main contributor to the development of resistance."

WEAK / review-level: a focused review synthesizing preclinical studies names MYC amplification as a main resistance contributor to multiselective tri-complex RAS(ON) inhibitors; primary drug-matched PDAC data are needed.

Immunosuppressive TME Reversibility under RAS(ON) Inhibition

Mechanism node for the immune-remodeling hypothesis: the immunosuppressive, T-cell-excluded microenvironment of PDAC is substantially RAS-activity-dependent and partially reversible by RAS-pathway inhibition, which promotes effector immune infiltration but requires checkpoint-blockade combination for durable regression. Daraxonrasib-specific PDAC immune data are still limited (strongest data use the G12D-selective MRTX1133).

Show evidence (1 reference)

PMID:37782788 SUPPORT Model Organism

"Lowering KRAS activity in established tumors promotes immune infiltration, but with a limited antitumor effect, whereas combining KRAS/MEK inhibition with immune checkpoint blockade achieves durable regression in preclinical models."

Establishes that the tumor immune composition tracks RAS activity and that RAS-pathway inhibition remodels it but needs checkpoint-blockade combination for durable benefit.

Myeloid Suppression Relief and CD8 Effector Infiltration

RAS-pathway inhibition decreases intratumoral myeloid infiltration, increases CD8+ effector T cells, and reprograms cancer-associated fibroblasts. Demonstrated with the G12D-selective MRTX1133 rather than daraxonrasib.

ras on inhibition immune tme remodeling

CD8-positive effector T cell CL:0000625 ↑ INCREASED

Downstream

Immunosuppressive TME Reversibility under RAS(ON) Inhibition Relief of myeloid suppression and CD8 infiltration are components of the RAS-dependent immune reversal.

Show evidence (1 reference)

PMID:37625401 SUPPORT Model Organism

"Employing 16 different models of KRASG12D-driven PDAC, we demonstrate that MRTX1133 reverses early PDAC growth, increases intratumoral CD8+ effector T cells, decreases myeloid infiltration, and reprograms cancer-associated fibroblasts."

Strong PDAC-model support for myeloid relief and CD8 effector infiltration; PARTIAL because it is achieved with the G12D-selective MRTX1133, not multiselective daraxonrasib.

Tumor-Cell FAS Induction and CD8-Mediated Killing

RAS/KRAS-G12D inhibition induces tumor-cell FAS, enabling CD8+ T-cell-mediated killing; regression of advanced PDAC requires CD8+ T cells and synergizes with checkpoint blockade (preclinical, MRTX1133).

ras on inhibition immune tme remodeling

Downstream

Immunosuppressive TME Reversibility under RAS(ON) Inhibition FAS-enabled CD8 killing is an effector arm of the RAS-dependent immune reversal.

Show evidence (1 reference)

PMID:36824971 SUPPORT Model Organism

"Regression of advanced PDAC requires CD8 + T cells and immune checkpoint blockade therapy (iCBT) synergizes with MRTX1133 to eradicate PDAC and prolong overall survival."

CD8-dependent, checkpoint-synergistic regression on RAS-G12D inhibition; PARTIAL because the agent is the G12D-selective MRTX1133, not daraxonrasib.

Antigen Presentation Restoration

Proposed increase in tumor antigen presentation on RAS(ON) inhibition. WEAK and competing for PDAC: MHC-I/antigen presentation in PDAC is largely autophagy(NBR1)- and FAK-controlled and only weakly RAS-owned; the direct daraxonrasib evidence is in NSCLC, not PDAC.

ras on inhibition immune tme remodeling

antigen processing and presentation GO:0019882 ↑ INCREASED

Downstream

Immunosuppressive TME Reversibility under RAS(ON) Inhibition A weakly RAS-owned, competing contribution to immune reversal.

Show evidence (1 reference)

PMID:41670434 SUPPORT Model Organism

"in immune-competent preclinical models, the RAS(ON) inhibitor doublet enhances tumor immune recognition by boosting antigen presentation and remodeling the suppressive tumor microenvironment, thus promoting immune-dependent complete regressions and sensitization of an immunorefractory model to..."

WEAK / competing for PDAC: the daraxonrasib-containing evidence for boosted antigen presentation is in KRAS-G12C NSCLC; in PDAC, MHC-I is dominantly autophagy(NBR1)/FAK-controlled and largely RAS-independent.

Regulatory T-Cell Relief

Proposed relief of regulatory-T-cell dominance on RAS/daraxonrasib inhibition. UNSUPPORTED source absence: a targeted literature search found no primary evidence that RAS or daraxonrasib inhibition depletes or disarms Tregs in PDAC. Retained here as an explicitly unverified edge for the immune-remodeling hypothesis, pending direct Treg profiling.

ras on inhibition immune tme remodeling

regulatory T cell CL:0000815

Downstream

Immunosuppressive TME Reversibility under RAS(ON) Inhibition Proposed but currently unsupported contribution (source absence); no primary PDAC evidence found.

USP20 Cholesterol-Metabolism CD8 Exhaustion Checkpoint

KRAS-G12D upregulates USP20 (via EGR1) to drive cholesterol metabolism and CD8+ T-cell exhaustion; RAS inhibition reverses this exhaustion axis but triggers compensatory ULK1 autophagy, so co-targeting cholesterol metabolism and autophagy potentiates KRAS-inhibitor efficacy. Human-tissue-anchored.

ras on inhibition immune tme remodeling

Downstream

Immunosuppressive TME Reversibility under RAS(ON) Inhibition Reversal of the cholesterol-driven CD8-exhaustion program contributes to RAS-dependent immune reversal.

Show evidence (1 reference)

PMID:42392864 SUPPORT Model Organism

"We found that KRASG12D enhanced cholesterol metabolism and promoted CD8+ T cell exhaustion, whereas KRASG12D inhibition or cholesterol synthesis blockade induced compensatory ULK1-associated autophagy."

Adds a human-anchored metabolic-immune layer: KRAS drives a cholesterol/ USP20-mediated CD8-exhaustion program reversed by RAS inhibition, with a compensatory autophagy escape that gates KRAS-inhibitor immune efficacy.

CDK8-CXCL2 Adaptive Immune Reversal

Durability-limiting counter-program: with long-term KRAS-G12D-inhibitor or daraxonrasib treatment, CDK8 remodels the microenvironment (CXCL2 chemokine secretion, FAS suppression) and reverses the initial immune gains, driving resistance. Bridges the immune-remodeling and resistance hypotheses.

ras on inhibition immune tme remodeling ras on inhibitor acquired resistance

Downstream

Acquired RAS(ON) Inhibitor Resistance CDK8-mediated reversal of immune remodeling drives adaptive resistance.

Show evidence (1 reference)

PMID:42436354 SUPPORT Model Organism

"long-term treatment results in reversal of the immune responses leading to resistance promoted by multiprotein mediator complex associated kinase CDK8."

CDK8-driven reversal of the immune-remodeling window is a durability limit that converts the therapeutic immune response into a resistance driver; names daraxonrasib explicitly.

✶

Histopathology

Pancreatic Ductal Adenocarcinoma VERY_FREQUENT

Malignant gland-forming ductal adenocarcinoma is the dominant histopathologic pattern in PDAC.

Desmoplastic Stroma VERY_FREQUENT

Dense collagen-rich fibrotic stroma surrounding malignant glands is a defining histopathologic feature of PDAC.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Digestive 3

Pancreatic Adenocarcinoma OBLIGATE HP:0006725

Show evidence (1 reference)

PMID:32593337 SUPPORT Human Clinical

"Pancreatic cancer is a highly fatal disease with a 5-year survival rate of approximately 10% in the USA, and it is becoming an increasingly common cause of cancer mortality."

The Lancet seminar confirms pancreatic cancer as a highly fatal malignancy with approximately 10% 5-year survival.

Obstructive Jaundice FREQUENT Cholestasis HP:0001396

Hepatic Metastases VERY_FREQUENT Neoplasm of the liver HP:0002896

Show evidence (1 reference)

PMID:36776324 SUPPORT Human Clinical

"There was a highest incidence of liver metastases from pancreatic cancer (2387,74.36%), followed by lung (625,19.47%), bone (190,5.92%), and brain (8,0.25%)."

This population-based study of metastatic PDAC directly identifies liver metastases as the most common distant metastatic site at diagnosis.

Endocrine 1

New-Onset Diabetes FREQUENT Type II diabetes mellitus HP:0005978

Show evidence (1 reference)

PMID:28507210 SUPPORT Human Clinical

"The relationships between diabetes and pancreatic ductal adenocarcinoma (PDAC) are complex. Longstanding type 2 diabetes (T2DM) is a risk factor for pancreatic cancer, but increasing epidemiological data point to PDAC as also a cause of diabetes due to unknown mechanisms."

Andersen et al. establish that PDAC causes new-onset diabetes through unknown mechanisms, demonstrating the bidirectional relationship between PDAC and diabetes.

Constitutional 3

Abdominal Pain VERY_FREQUENT HP:0002027

Show evidence (2 references)

PMID:25726049 SUPPORT Human Clinical

"Common signs and symptoms of PDA include abdominal or back pain, jaundice, weight loss, pruritus, and nausea/vomiting."

Directly lists abdominal pain as a common presenting symptom of pancreatic ductal adenocarcinoma.

PMID:32593337 SUPPORT Human Clinical

"Patients typically present with advanced disease due to lack of or vague symptoms when the cancer is still localised."

The Lancet review notes that patients present with advanced disease due to vague early symptoms, consistent with abdominal pain as a common late presentation.

Fatigue HP:0012378

Back pain FREQUENT HP:0003418

Show evidence (1 reference)

PMID:25726049 SUPPORT Human Clinical

"Common signs and symptoms of PDA include abdominal or back pain, jaundice, weight loss, pruritus, and nausea/vomiting."

Directly lists back pain as a common presenting symptom of pancreatic ductal adenocarcinoma.

Growth 1

Weight Loss VERY_FREQUENT HP:0001824

Show evidence (1 reference)

PMID:28507210 SUPPORT Human Clinical

"most patients with PDAC report weight loss rather than weight gain. The clinical features of deteriorating glycemic control in conjunction with weight loss that accompanies PDAC prior to its diagnosis are atypical for T2DM"

Andersen et al. note that weight loss is a characteristic clinical feature of PDAC, distinguishing it from typical T2DM presentation.

🧬

Genetic Associations

KRAS (Somatic Gain-of-Function Mutation)

Gene: KRAS hgnc:6407

Somatic

Show evidence (2 references)

PMID:33347393 SUPPORT Human Clinical

"This systematic review and meta-analysis supports the use of driver mutations in the P53, SMAD4, and KRAS genes as prognostic markers for pancreatic cancer."

Directly supports KRAS as an established driver mutation and prognostic marker in pancreatic cancer.

DOI:10.3389/fmed.2024.1369136 SUPPORT Human Clinical

"In the case of pancreatic ductal adenocarcinomas (PDAC), 90-92% harbor mutations in the oncogene KRAS, triggering canonical MAPK signaling. The smooth structure of the altered KRAS protein without a binding pocket and its affinity for GTP have, in the past, hampered drug development."

Confirms KRAS mutations in 90-92% of PDAC and describes the structural challenges that have historically hampered therapeutic targeting of KRAS.

TP53 (Somatic Loss-of-Function Mutation)

Gene: TP53 hgnc:11998

Somatic

Show evidence (1 reference)

PMID:37404765 SUPPORT Human Clinical

"the KRAS mutated group had a significantly higher percentage of TP53 (mutated vs wild-type: 80.2% vs 47.6%, p <0.0001)"

Foundation Medicine genomic profiling of 9,444 advanced PDAC cases showed TP53 mutations in 80.2% of KRAS-mutated PDAC.

SMAD4 (Somatic Loss-of-Function Mutation)

Gene: SMAD4 hgnc:6770

Somatic

Show evidence (1 reference)

PMID:37404765 SUPPORT Human Clinical

"SMAD4 (mutated vs wild-type: 26.8% vs 15.7%, p <0.0001)"

Foundation Medicine profiling showed SMAD4 mutations in 26.8% of KRAS-mutated PDAC. Higher rates reported in other studies reflect inclusion of homozygous deletions not captured by all assays.

CDKN2A (Somatic Loss-of-Function Mutation)

Gene: CDKN2A hgnc:1787

Somatic

Show evidence (2 references)

PMID:18772397 SUPPORT Human Clinical

"This list includes the classic tumor suppressor genes CDKN2A (p16), SMAD4, and TP53, as well as genes that had not previously been implicated in pancreatic cancer development."

Directly identifies CDKN2A/p16 as a classic tumor suppressor gene affected by homozygous deletion in pancreatic cancers.

PMID:37404765 SUPPORT Human Clinical

"CDKN2A (mutated vs wild-type: 56.2% vs 34.4%, p <0.0001)"

Foundation Medicine profiling showed CDKN2A alterations in 56.2% of KRAS-mutated PDAC. Higher rates in other studies include epigenetic silencing.

BRCA2 (Germline and Somatic Mutation)

Gene: BRCA2 hgnc:1101

Somatic

Show evidence (1 reference)

PMID:31157963 SUPPORT Human Clinical

"Patients with a germline BRCA1 or BRCA2 mutation make up a small subgroup of those with metastatic pancreatic cancer. The poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor olaparib has had antitumor activity in this population."

The POLO trial confirmed that BRCA-mutated PDAC patients represent a distinct subgroup that responds to PARP inhibition, validating the clinical relevance of BRCA2 mutations in PDAC.

💊

Medical Actions

Surgical Resection (Whipple Procedure)

Action: pancreaticoduodenectomy (Whipple procedure) Ontology label: Whipple Procedure NCIT:C15356

Pancreaticoduodenectomy (Whipple procedure) is the only potentially curative treatment for PDAC but is feasible in only 15-20% of patients at diagnosis. R0 resection followed by adjuvant chemotherapy provides the best long-term survival outcomes.

Show evidence (1 reference)

PMID:28129987 SUPPORT Human Clinical

"Eligible patients were aged 18 years or older and had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1 resection)."

The ESPAC-4 trial enrolled patients who underwent complete macroscopic resection for PDAC, confirming surgical resection as a standard treatment approach with adjuvant chemotherapy improving outcomes.

FOLFIRINOX Chemotherapy

Action: chemotherapy Ontology label: Chemotherapy NCIT:C15632 Regimen: modified FOLFIRINOX regimen Ontology label: Folfirinox Regimen NCIT:C11764

Combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin. Used as first-line treatment for metastatic PDAC in fit patients and as adjuvant therapy after surgical resection. Provides superior survival compared to gemcitabine alone but with greater toxicity.

Show evidence (1 reference)

PMID:30575490 SUPPORT Human Clinical

"Adjuvant therapy with a modified FOLFIRINOX regimen led to significantly longer survival than gemcitabine among patients with resected pancreatic cancer, at the expense of a higher incidence of toxic effects."

The PRODIGE 24 trial demonstrated that adjuvant modified FOLFIRINOX significantly improved disease-free and overall survival compared to gemcitabine in resected PDAC patients.

Gemcitabine-Based Chemotherapy

Action: chemotherapy Ontology label: Chemotherapy NCIT:C15632

Gemcitabine monotherapy or in combination with nab-paclitaxel is a standard treatment for advanced PDAC. Gemcitabine plus nab-paclitaxel provides improved survival over gemcitabine alone and is better tolerated than FOLFIRINOX.

Show evidence (1 reference)

PMID:24131140 SUPPORT Human Clinical

"nab-paclitaxel plus gemcitabine significantly improved overall survival, progression-free survival, and response rate, but rates of peripheral neuropathy and myelosuppression were increased."

The Von Hoff et al. phase 3 trial demonstrated that nab-paclitaxel plus gemcitabine significantly improved overall survival (8.5 vs 6.7 months) in metastatic pancreatic adenocarcinoma.

PARP Inhibitor Therapy

Action: targeted therapy Ontology label: Targeted Therapy NCIT:C93352

Olaparib is approved as maintenance therapy for BRCA-mutated metastatic PDAC that has not progressed on first-line platinum-based chemotherapy, based on the POLO trial.

Show evidence (2 references)

DOI:10.1200/jco.21.01604 SUPPORT Human Clinical

"The phase III POLO study demonstrated significant progression-free survival (PFS) benefit for active olaparib maintenance therapy versus placebo for patients with metastatic pancreatic adenocarcinoma and a germline BRCA mutation."

The phase III POLO trial supports maintenance olaparib in germline BRCA-mutated metastatic pancreatic adenocarcinoma; folded in from the former Metastatic_Pancreatic_Adenocarcinoma entry.

PMID:31157963 SUPPORT Human Clinical

"We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy of olaparib as maintenance therapy in patients who had a germline BRCA1 or BRCA2 mutation and metastatic pancreatic cancer and disease that had not progressed during first-line platinum-based chemotherapy."

The POLO trial demonstrated that maintenance olaparib significantly prolonged progression-free survival in germline BRCA-mutated metastatic pancreatic cancer patients who had not progressed on platinum-based chemotherapy.

Daraxonrasib (RAS(ON) Multiselective Inhibitor)

Action: Pharmacotherapy NCIT:C15986

Agent: daraxonrasib CHEBI:746946

Daraxonrasib (RMC-6236) is an oral RAS(ON) multiselective, tri-complex inhibitor that binds cyclophilin A intracellularly to engage the active GTP-bound state of mutant and wild-type RAS (KRAS, NRAS, and HRAS, including G12, G13, and Q61 variants) and suppress downstream MAPK signaling. In the phase 3 RASolute 302 trial in previously treated metastatic PDAC, daraxonrasib doubled median overall survival to 13.2 months versus 6.6 months with chemotherapy in the RAS G12 population (hazard ratio 0.40), directly drugging the near-universal KRAS oncogenic driver of PDAC that had long been considered undruggable.

Mechanism Target:

INHIBITS KRAS Oncogene Activation — Daraxonrasib directly inhibits the active RAS(ON) state produced by oncogenic KRAS codon-12 mutations, the initiating driver of PDAC, suppressing constitutive RAS-MAPK signaling.

Show evidence (1 reference)

PMID:42223072 SUPPORT Human Clinical

"Daraxonrasib is an oral RAS(ON) multiselective, tri-complex inhibitor of the active guanosine triphosphate-bound state of mutant and wild-type RAS."

The RASolute 302 report describes daraxonrasib's mechanism as direct inhibition of the active GTP-bound RAS state driven by mutant KRAS in PDAC.

Show evidence (4 references)

clinicaltrials:NCT06625320 SUPPORT Human Clinical

"The purpose of this study is to evaluate the safety and efficacy of a novel RAS(ON) inhibitor compared to standard(s) of care (SOC) treatment."

ClinicalTrials.gov documents RASolute 302 as a phase 3 evaluation of the RAS(ON) inhibitor daraxonrasib versus standard-of-care chemotherapy in previously treated metastatic PDAC.

PMID:42223072 SUPPORT Human Clinical

"Daraxonrasib is an oral RAS(ON) multiselective, tri-complex inhibitor of the active guanosine triphosphate-bound state of mutant and wild-type RAS."

Establishes daraxonrasib's mechanism of action as a RAS(ON) multiselective tri-complex inhibitor of the active GTP-bound state of mutant and wild-type RAS, the basis for its target_mechanisms link to KRAS-centered signaling.

PMID:42223072 SUPPORT Human Clinical

"The median overall survival in the RAS G12 population was 13.2 months with daraxonrasib and 6.6 months with chemotherapy, and the median overall survival in the overall population was 13.2 months and 6.7 months, respectively; the hazard ratio was 0.40 in both populations (P<0.001)."

RASolute 302 demonstrated a significant overall survival benefit for daraxonrasib over chemotherapy (hazard ratio for death 0.40) in previously treated metastatic PDAC.

+ 1 more reference

Mutant KRAS Vaccine (Immunologic Interception)

Action: vaccination Ontology label: Vaccination NCIT:C15346

Because activating KRAS mutations (G12D, G12V, G12R) are the near-universal initiating event in PDAC and are shared across patients, the mutant KRAS protein is an attractive shared tumor neoantigen for vaccination — the basis of an "interception" strategy aiming to raise anti-mutant-KRAS T-cell immunity in high-risk individuals and in the minimal-residual-disease setting before macroscopic recurrence. In the phase 1 AMPLIFY-201 trial, the lymph-node-targeted amphiphile vaccine ELI-002 2P (G12D/G12R mKRAS peptides plus CpG adjuvant) induced mutant-KRAS-specific CD4+/CD8+ T-cell responses in most patients with KRAS-mutated pancreatic or colorectal cancer. Application as true primary prevention in high-risk individuals is under investigation.

Mechanism Target:

INHIBITS KRAS Oncogene Activation — The vaccine presents mutant-KRAS neoantigens to prime cytotoxic and helper T cells that recognize and eliminate cells expressing the oncogenic KRAS variant — an immunologic route to suppressing the KRAS-driven clone, distinct from direct pharmacologic RAS inhibition.

Show evidence (1 reference)

PMID:38195752 SUPPORT Human Clinical

"ELI-002 2P was safe and induced considerable T cell responses in patients with immunotherapy-recalcitrant KRAS-mutated tumors."

Demonstrates that a mutant-KRAS vaccine induces mKRAS-specific T-cell responses in KRAS-mutated tumors, supporting immune targeting of the KRAS-oncogene-activated clone.

Show evidence (1 reference)

PMID:38195752 SUPPORT Human Clinical

"Cancer vaccine ELI-002 2P enhances lymph node delivery and immune response using amphiphile (Amph) modification of G12D and G12R mutant KRAS (mKRAS) peptides (Amph-Peptides-2P) together with CpG oligonucleotide adjuvant (Amph-CpG-7909)."

Describes the mutant-KRAS amphiphile vaccine platform evaluated in the phase 1 AMPLIFY-201 trial.

🌍

Environmental Factors

Tobacco Smoking

Cigarette smoking is the most well-established modifiable risk factor for PDAC, approximately doubling the risk. Tobacco carcinogens are metabolized in the pancreas and may promote KRAS mutations.

Show evidence (2 references)

PMID:34002083 SUPPORT Human Clinical

"there are key modifiable risk factors for pancreatic cancer such as cigarette smoking, obesity, diabetes and alcohol intake."

Directly identifies cigarette smoking as a leading modifiable risk factor for pancreatic cancer.

PMID:24509242 SUPPORT Human Clinical

"Current tobacco use was the single most important risk factor for pancreatic diseases (RR, 1.87; 95% CI, 1.54-2.27)"

Meta-analysis of 51 population-based prospective cohort studies identified tobacco use as the single most important modifiable risk factor for pancreatic diseases with an RR of 1.87. The outcome measured is pancreatic diseases as a class, and the same abstract reports that tobacco has a bigger effect on acute and chronic pancreatitis than on pancreatic cancer, so this figure is not a cancer-specific estimate.

Mechanism Target:

PREDISPOSES KRAS Oncogene Activation — Pointed at the node this entry calls the initiating oncogenic event, because that is where a carcinogen exposure enters the graph. The route is left unknown deliberately: this entry's own description proposes that tobacco carcinogens promote KRAS mutations, but no cited sentence says so. The second item is carried precisely because it limits the first, and the limit is easy to miss: the headline relative risk is for pancreatic diseases as a class, and the same abstract reports that tobacco's effect on pancreatitis is larger than its effect on pancreatic cancer.

Show evidence (2 references)

PMID:24509242 SUPPORT Human Clinical

"Current tobacco use was the single most important risk factor for pancreatic diseases (RR, 1.87; 95% CI, 1.54-2.27), followed by obesity (RR, 1.48; 95% CI, 1.15-1.92) and heavy use of alcohol (RR, 1.37; 95% CI, 1.19-1.58)"

Meta-analysis of 51 prospective cohorts giving tobacco the largest relative risk of the factors examined. Quoted whole so the comparison with obesity and alcohol travels with it. The outcome is pancreatic diseases, not this node.

PMID:24509242 SUPPORT Human Clinical

"Tobacco and heavy use of alcohol had bigger effects on risk of acute pancreatitis and chronic pancreatitis than pancreatic cancer"

The same abstract's own qualifier: the tobacco effect is larger for acute and chronic pancreatitis than for pancreatic cancer. Carried here so the headline figure is not read as a cancer-specific estimate.

PREDISPOSES Chronic Pancreatic Inflammation — The second link, added once the entry had an inflammation node to receive it. This is where the cited meta-analysis's evidence is actually strongest: the qualifier that limits the KRAS link above - that tobacco's effect on pancreatitis exceeds its effect on pancreatic cancer - is direct support here. The route from smoke constituents to pancreatic inflammation is not traced by the abstract, so the intermediates stay unknown.

Show evidence (1 reference)

PMID:24509242 SUPPORT Human Clinical

"Tobacco and heavy use of alcohol had bigger effects on risk of acute pancreatitis and chronic pancreatitis than pancreatic cancer"

Names chronic pancreatitis as an outcome on which tobacco acts more strongly than on the cancer, which is the node this link targets.

Chronic Pancreatitis

Chronic pancreatitis is a disease state rather than an exposure, so this entry sits in the class of `environmental:` items discussed in issue #8185. The comorbidity now exists -- `kb/comorbidities/com_Chronic_Pancreatitis__Pancreatic_Ductal_Adenocarcinoma.yaml`, added in dismech#8296 -- and this row is deliberately kept rather than folded into it, which resolves the open question this note previously recorded. The two divide the labour. This row carries the mechanistic route into the pathograph: the `influences_mechanisms` link onto Chronic Pancreatic Inflammation, with the KRAS-mutant mouse experiment that shows inducing pancreatitis is sufficient to release the neoplastic sequence. A comorbidity entry has no pathograph link to offer, so folding this row in would lose that. The comorbidity carries the disease-disease epidemiology as a directed, queryable A_BEFORE_B risk edge with a magnitude. Both cite PMID:35142721; the comorbidity additionally carries the 1993 cohort standardized incidence ratio, which this row does not need.

Long-standing chronic pancreatitis increases PDAC risk approximately 10-15 fold. Chronic inflammation promotes ductal cell proliferation and accumulation of oncogenic mutations.

Show evidence (1 reference)

PMID:35142721 SUPPORT Human Clinical

"There is an increased risk of PDAC in patients with CP, and incidence rates increase with CP disease duration."

Gandhi et al. meta-analysis demonstrated a 22.6-fold increased risk of PDAC in chronic pancreatitis patients, with risk persisting after excluding surveillance bias.

Mechanism Target:

TRIGGERS Chronic Pancreatic Inflammation — Retargeted from KRAS Oncogene Activation once this entry modeled the inflammation it acts on. Nothing intervenes: sustained pancreatic inflammation is what chronic pancreatitis is, so this is the one link in the block where the exposure and the node it reaches are the same process rather than separated by an untraced route.

Show evidence (2 references)

PMID:35142721 SUPPORT Human Clinical

"There is an increased risk of PDAC in patients with CP, and incidence rates increase with CP disease duration."

Cancer specific and dose-responsive, which is why it is the strongest of the three exposures here. PARTIAL because it measures cancer incidence rather than the inflammation this link targets.

PMID:17349585 SUPPORT Model Organism

"However, if these mice are challenged with a mild form of chronic pancreatitis, they develop the full spectrum of PanINs and invasive PDA."

The experimental counterpart: inducing chronic pancreatitis is what supplies the inflammatory state this link targets, and doing so is sufficient to release the neoplastic sequence in KRAS-mutant animals.

Obesity and Diet

Obesity and high body mass index are associated with increased PDAC risk. High-fat diets and processed meat consumption have also been linked to elevated risk.

Show evidence (1 reference)

PMID:24509242 SUPPORT Human Clinical

"followed by obesity (RR, 1.48; 95% CI, 1.15-1.92)"

Meta-analysis of prospective cohort studies identified obesity as the second most important risk factor for pancreatic diseases with an RR of 1.48.

Mechanism Target:

PREDISPOSES Chronic Pancreatic Inflammation — Retargeted from KRAS Oncogene Activation. The limitation that made this link weak against the oncogene - that the meta-analysis measures pancreatic diseases as a class rather than the cancer - is much less of a stretch against an inflammation node, since pancreatitis is one of the diseases in that class. The route from adiposity to pancreatic inflammation is still not traced by the abstract, so the intermediates stay unknown, and the diet half of this exposure is not separately evidenced here at all.

Show evidence (1 reference)

PMID:24509242 SUPPORT Human Clinical

Gives obesity the second largest relative risk in the same ranking. Quoted whole rather than as the obesity clause alone, so that the exposure's rank among the others is visible.

🔬

Biochemical Markers

CA 19-9

Show evidence (1 reference)

PMID:23331006 SUPPORT Human Clinical

"In 57 studies involving 3,285 pancreatic carcinoma cases, the combined sensitivity of CA 19-9 was 78.2% and in 37 studies involving 1,882 cases with benign pancreatic disease the specificity of CA 19-9 was 82.8%."

Poruk et al. meta-analysis established CA 19-9 sensitivity of 78.2% and specificity of 82.8% for pancreatic carcinoma diagnosis.

Carcinoembryonic Antigen (CEA)

Show evidence (1 reference)

PMID:23331006 SUPPORT Human Clinical

"From the combined analysis of studies reporting CEA, the sensitivity was 44.2% (1,324 cases) and the specificity was 84.8% (656 cases)."

Poruk et al. meta-analysis showed CEA has lower sensitivity (44.2%) than CA 19-9 but comparable specificity (84.8%) for pancreatic carcinoma.

🪜

Stages

Localized

Resectable or borderline-resectable disease confined to the pancreas and regional nodes, treated with resection (Whipple procedure) plus perioperative or adjuvant chemotherapy.

Metastatic

Advanced pancreatic ductal adenocarcinoma with distant spread, most commonly hepatic and peritoneal. The metastatic state is dominated by early dissemination, neural invasion, and stromal exclusion of antitumor immunity; RAS(ON) multiselective inhibition and its resistance and immune-reversal biology are modeled on this entry's dedicated pathophysiology nodes.

Folded in from the former Metastatic_Pancreatic_Adenocarcinoma entry (cancer granularity ladder, design decisions §3a). The 5-year survival rate remains persistently low in PDAC, especially once metastatic dissemination is established (PMID:41814069).

📊

Related Datasets

Integrating microarray-based spatial transcriptomics and single-cell RNA-seq reveals tissue architecture in pancreatic ductal adenocarcinomas geo:GSE111672

Multimodal PDAC dataset combining spatial transcriptomics and single-cell RNA-seq from primary pancreatic tumors. Useful for resolving how malignant ductal cells, macrophages, dendritic cells, and fibroblast states are spatially organized within the tumor microenvironment.

human MULTI OMICS n=23

pancreatic tumor tissue UBERON:0001264

Conditions: primary pancreatic ductal adenocarcinoma

PMID:31932730

GEO reports six primary pancreatic cancer patients with matched single-cell and spatial transcriptomic profiling. Particularly relevant for spatial initialization and cell-neighborhood constraints in PhysiCell-style TME models.

Single-cell transcriptomics analysis of pancreatic primary tumor and metastatic biopsy tissues geo:GSE154778

Single-cell RNA-seq of 10 pancreatic primary tumors and 6 metastatic biopsies. Captures tumor, stromal, and immune programs across primary and metastatic disease, making it useful for modeling dissemination and metastatic niche adaptation in PDAC.

human SINGLE CELL RNA SEQ n=16

pancreatic tumor tissue UBERON:0001264

Conditions: primary pancreatic ductal adenocarcinoma metastatic pancreatic ductal adenocarcinoma

PMID:32988401

GEO reports 10 primary tumors and 6 metastatic lesion biopsies profiled on the 10x Genomics Chromium platform. High-value bridge dataset between primary-tumor ecology and metastatic evolution.

Multimodal Mapping of the Tumor and Peripheral Blood Immune Landscape in Human Pancreatic Cancer geo:GSE155698

Single-cell immune-focused PDAC resource spanning tumor tissue, adjacent normal pancreas, and peripheral blood mononuclear cells from pancreatic cancer patients, plus healthy-donor PBMC controls. Especially useful for linking the local TME to the systemic macroenvironment.

human SINGLE CELL RNA SEQ n=41

pancreatic tumor tissue UBERON:0001264 adjacent normal pancreatic tissue UBERON:0001264 peripheral blood UBERON:0000178

Conditions: pancreatic ductal adenocarcinoma tumor tissue adjacent normal pancreas pancreatic cancer patient PBMCs healthy donor PBMCs

PMID:34296197

GEO reports 16 PDAC tissue samples, 3 adjacent normal pancreas samples, 16 patient PBMC samples, and 4 healthy-donor PBMC samples. This is a strong anchor for modeling immune composition across tumor and circulation.

Microarray gene-expression profiles of 69 pancreatic tumors and 61 adjacent non-tumor tissue from patients with pancreatic ductal adenocarcinoma geo:GSE62452

Large paired bulk expression cohort of PDAC tumors and adjacent non-tumor tissue. Useful as a broader transcriptomic reference set for tumor-versus-normal contrasts and for anchoring subtype-level or pathway-level signatures in a larger patient cohort.

human MICROARRAY n=130

pancreatic tumor tissue UBERON:0001264

Conditions: pancreatic ductal adenocarcinoma tumor tissue adjacent non-tumor pancreatic tissue

PMID:27197190

GEO reports 69 pancreatic tumors and 61 adjacent non-tumor tissues, with earlier Affymetrix data from GSE28735 incorporated into the merged normalized cohort. Useful as a bulk-expression complement to the single-cell and spatial resources above.

🔬

Clinical Trials

NCT06625320 PHASE_III ACTIVE_NOT_RECRUITING

RASolute 302: a phase 3, international, open-label, randomized trial comparing daraxonrasib (RMC-6236) with the investigator's choice of standard chemotherapy in patients with previously treated metastatic PDAC. The trial met its dual primary endpoints of overall survival and progression-free survival in the RAS G12 population.

Target Phenotypes: Neoplasm of the pancreas HP:0002894

Show evidence (2 references)

clinicaltrials:NCT06625320 SUPPORT Human Clinical

"The purpose of this study is to evaluate the safety and efficacy of a novel RAS(ON) inhibitor compared to standard(s) of care (SOC) treatment."

ClinicalTrials.gov confirms RASolute 302 (NCT06625320) evaluated the RAS(ON) inhibitor daraxonrasib against standard-of-care chemotherapy in mPDAC.

PMID:42223072 SUPPORT Human Clinical

"Among patients with previously treated mPDAC, treatment with daraxonrasib led to significantly longer overall survival and progression-free survival than chemotherapy."

The primary-results publication reports that RASolute 302 met its overall survival and progression-free survival endpoints favoring daraxonrasib.

🧮

Computational Models

PDAC CAF-Mediated Invasion PhysiCell Model C++/XML/CSV PhysiCell AGENT_BASED

Grammar-based PhysiCell agent-based model of pancreatic ductal adenocarcinoma neoplastic cells and cancer-associated fibroblasts. The model encodes fibroblast-mediated invasion, epithelial-mesenchymal state switching, and ECM-dependent motility tradeoffs using human-interpretable cell rules informed by PDAC spatial transcriptomics and coculture data.

Repository ↗ DOI:10.1016/j.cell.2025.06.048 Base model: PhysiCell grammar manuscript release DOI:10.5281/zenodo.16285252

Variable	Model ID	Unit	Ontology Mappings
inflammatory_signal Generic inflammatory signaling field used to bias migration and mesenchymal-to-epithelial state transitions.	`inflammatory_signal`	dimensionless field
ecm Extracellular-matrix density field driving stromal invasion and epithelial-mesenchymal plasticity.	`ecm`	dimensionless field	Extracellular matrix
epithelial_normal_cells Abundance of non-malignant epithelial agents in the coculture invasion simulation.	`epithelial_normal`	cells	epithelial cell
mesenchymal_normal_cells Abundance of non-malignant mesenchymal-state agents in the invasion simulation.	`mesenchymal_normal`	cells	mesenchymal cell
fibroblast_cells Abundance of fibroblast / CAF-like agents in the invasion simulation.	`fibroblast`	cells	fibroblast
epithelial_tumor_cells Abundance of epithelial-state malignant agents in the invasion simulation.	`epithelial_tumor`	cells	epithelial tumor cell
mesenchymal_tumor_cells Abundance of mesenchymal-state malignant agents in the invasion simulation.	`mesenchymal_tumor`	cells	mesenchymal tumor cell

Pathograph links

Desmoplastic Stroma Implements ECM-driven fibroblast motility and epithelial-mesenchymal state switching encoded in `config/cell_rules.csv` for the stromal invasion program.

Findings

ECM increases epithelial-to-mesenchymal switching of tumor epithelial cells in the executable PDAC invasion model.

"epithelial_tumor,ecm,increases,transform to mesenchymal_tumor,0.01,0.01,4,0"

Fibroblast migration is explicitly controlled by ECM-dependent rules in the invasion model.

"fibroblast,ecm,increases,migration speed,3.470551875,9.999679617,1.153017946,0"

Manuscript-synced sample model from the official PhysiCell grammar_samples release. Relevant configs include `config/PhysiCell_settings_PDAC.xml`, the rule table in `config/cell_rules.csv`, and coculture initial conditions under `config/ics/`.

PDAC Immunotherapy PhysiCell Model C++/XML/CSV PhysiCell AGENT_BASED

Grammar-based PhysiCell agent-based PDAC tumor-immune model initialized from PDAC tissue compositions. The model simulates combination therapy with GVAX, nivolumab, and urelumab across heterogeneous baseline microenvironment states and is a strong executable analogue of PDAC immune-excluded ecology.

Repository ↗ DOI:10.1016/j.cell.2025.06.048 Base model: PhysiCell grammar manuscript release DOI:10.5281/zenodo.16285252

Variable	Model ID	Unit	Ontology Mappings
oxygen Diffusible oxygen field used to control tumor proliferation, macrophage polarization logic, and necrotic stress.	`oxygen`	substrate density	dioxygen
debris Extracellular dead-cell debris field that attracts macrophages and reflects local cell death burden.	`debris`	substrate density
pro_inflammatory_factor Generic pro-inflammatory signaling field that boosts T-cell attack and chemotaxis in the model.	`pro-inflammatory factor`	substrate density
anti_inflammatory_factor Generic anti-inflammatory signaling field that suppresses T-cell migration and attack in the model.	`anti-inflammatory factor`	substrate density
PD-L1lo_tumor_cells Abundance of PD-L1-low malignant epithelial agents in the PDAC immunotherapy simulation.	`PD-L1lo_tumor`	cells	epithelial tumor cell
PD-L1hi_tumor_cells Abundance of PD-L1-high malignant epithelial agents in the PDAC immunotherapy simulation.	`PD-L1hi_tumor`	cells	epithelial tumor cell Programmed cell death 1 ligand 1
macrophages Abundance of macrophage agents in the PDAC immunotherapy simulation.	`macrophage`	cells	macrophage
PD-1hi_CD137lo_CD8_T_cells Abundance of PD-1-high CD137-low CD8 T-cell agents in the PDAC immunotherapy simulation.	`PD-1hi_CD137lo_CD8_Tcell`	cells	PD-1-high CD137-low CD8 T cell
PD-1lo_CD137lo_CD8_T_cells Abundance of PD-1-low CD137-low CD8 T-cell agents in the PDAC immunotherapy simulation.	`PD-1lo_CD137lo_CD8_Tcell`	cells	PD-1-low CD137-low CD8 T cell
PD-1hi_CD137hi_CD8_T_cells Abundance of PD-1-high CD137-high CD8 T-cell agents in the PDAC immunotherapy simulation.	`PD-1hi_CD137hi_CD8_Tcell`	cells	PD-1-high CD137-high CD8 T cell
PD-1lo_CD137hi_CD8_T_cells Abundance of PD-1-low CD137-high CD8 T-cell agents in the PDAC immunotherapy simulation.	`PD-1lo_CD137hi_CD8_Tcell`	cells	PD-1-low CD137-high CD8 T cell
PD-1hi_CD4_T_cells Abundance of PD-1-high CD4 T-cell agents in the PDAC immunotherapy simulation.	`PD-1hi_CD4_Tcell`	cells	PD-1-high CD4 T cell
PD-1lo_CD4_T_cells Abundance of PD-1-low CD4 T-cell agents in the PDAC immunotherapy simulation.	`PD-1lo_CD4_Tcell`	cells	PD-1-low CD4 T cell

Pathograph links

Immune Evasion Encodes PD-L1-dependent suppression of T-cell motility and attack probabilities, plus macrophage inflammatory-state rules, in `config/cell_rules.csv`.

Findings

Contact with PD-L1-high tumor cells reduces CD8 T-cell migration in the executable PDAC immunotherapy model.

"PD-1lo_CD137lo_CD8_Tcell,contact with PD-L1hi_tumor,decreases,migration speed,0,0.1,2,0"

Anti-inflammatory signals decrease CD8 T-cell attack against tumor cells in the executable PDAC immunotherapy model.

"PD-1lo_CD137hi_CD8_Tcell,anti-inflammatory factor,decreases,attack PD-L1hi_tumor,0,2.5,2,0"

Macrophage oxygen sensing controls pro- versus anti-inflammatory factor secretion in the executable PDAC immunotherapy model.

"macrophage,oxygen,decreases,anti-inflammatory factor secretion,0,5,4,0"

Manuscript-synced sample model from the official PhysiCell grammar_samples release. Therapy-specific initial-condition files are stored in `config/ic_cells/`, and the core executable interaction logic is in `config/cell_rules.csv`.

{ }

Source YAML

click to show

name: Pancreatic Ductal Adenocarcinoma
creation_date: "2026-03-06T00:00:00Z"
description: >-
  Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer,
  accounting for approximately 90% of pancreatic malignancies. It is characterized by
  near-universal KRAS oncogene mutations (~90%), frequent inactivation of tumor suppressors
  TP53, SMAD4, and CDKN2A, and a dense desmoplastic stroma that contributes to treatment
  resistance and immune evasion. PDAC has one of the worst prognoses of any solid tumor
  with a 5-year survival rate of approximately 12%. Standard treatments include surgical
  resection (Whipple procedure) for the minority with resectable disease, and
  gemcitabine-based or FOLFIRINOX chemotherapy regimens.
categories:
- Solid Tumor
- Gastrointestinal Cancer
- Adenocarcinoma
parents:
- pancreatic cancer
has_subtypes:
- name: Classical Subtype
  description: >-
    Characterized by expression of epithelial differentiation genes and transcription
    factors such as GATA6. Generally associated with better prognosis compared to
    basal-like subtype.
  evidence:
  - reference: PMID:26343385
    reference_title: "Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      we have identified and validated two tumor subtypes, including a 'basal-like'
      subtype that has worse outcome and is molecularly similar to basal tumors in
      bladder and breast cancers.
    explanation: >-
      Moffitt et al. used virtual microdissection of gene expression data to identify
      classical and basal-like subtypes of PDAC, with classical having better prognosis.
- name: Basal-like Subtype
  description: >-
    Characterized by expression of basal/squamous markers and loss of GATA6. Associated
    with worse prognosis, higher metastatic potential, and resistance to chemotherapy.
  evidence:
  - reference: PMID:26343385
    reference_title: "Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      patients with basal-like subtype tumors had an overall worse median survival of
      11 months and 44% 1-year survival compared to 19 months and 70% 1-year survival
      for those with classical subtype tumors
    explanation: >-
      Moffitt et al. demonstrated basal-like subtype has significantly worse survival
      compared to classical subtype in PDAC.
stages:
- name: Localized
  description: >-
    Resectable or borderline-resectable disease confined to the pancreas and
    regional nodes, treated with resection (Whipple procedure) plus
    perioperative or adjuvant chemotherapy.
- name: Metastatic
  description: >-
    Advanced pancreatic ductal adenocarcinoma with distant spread, most
    commonly hepatic and peritoneal. The metastatic state is dominated by
    early dissemination, neural invasion, and stromal exclusion of antitumor
    immunity; RAS(ON) multiselective inhibition and its resistance and
    immune-reversal biology are modeled on this entry's dedicated
    pathophysiology nodes.
  notes: >-
    Folded in from the former Metastatic_Pancreatic_Adenocarcinoma entry
    (cancer granularity ladder, design decisions §3a). The 5-year survival
    rate remains persistently low in PDAC, especially once metastatic
    dissemination is established (PMID:41814069).
pathophysiology:
- name: Chronic Pancreatic Inflammation
  conforms_to: "tumor_promoting_inflammation#Chronic Inflammatory Stimulus"
  description: >-
    Sustained inflammatory injury of the exocrine pancreas, the non-genetic half of
    PDAC initiation. Oncogenic KRAS on its own is not sufficient in the adult
    pancreas: the same allele that drives disease when expressed embryonically leaves
    adult mice refractory until the tissue is inflamed, at which point the full
    PanIN-to-carcinoma sequence follows. This node is what the entry's environmental
    exposures actually act on, and it is the substrate on which mutant KRAS becomes
    tumorigenic.
  biological_scale: TISSUE
  role: trigger
  locations:
  - preferred_term: pancreas
    term:
      id: UBERON:0001264
      label: pancreas
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: pancreatic stellate cell
    term:
      id: CL:0002410
      label: pancreatic stellate cell
  biological_processes:
  - preferred_term: inflammatory response
    modifier: INCREASED
    term:
      id: GO:0006954
      label: inflammatory response
  downstream:
  - target: Acinar-to-Ductal Metaplasia
    causal_link_type: DIRECT
    description: >-
      Inflammatory injury drives acinar cells out of their differentiated state and
      into a ductal-like phenotype, which is the metaplastic response this node's
      target models.
    evidence:
    - reference: PMID:17349585
      reference_title: Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "However, if these mice are challenged with a mild form of chronic pancreatitis, they develop the full spectrum of PanINs and invasive PDA."
      explanation: >-
        Inflaming the adult pancreas is what releases the block on the metaplastic and
        neoplastic sequence in KRAS-mutant animals, which is the dependency this edge
        asserts.
  evidence:
  - reference: PMID:17349585
    reference_title: Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These observations suggest that, during adulthood, PDA stems from a combination of genetic (e.g., somatic K-Ras mutations) and nongenetic (e.g., tissue damage) events."
    explanation: >-
      States the two-component model directly: the genetic lesion is modeled by the
      KRAS node and the nongenetic tissue-damage component is what this node is for.
  - reference: PMID:35142721
    reference_title: "Chronic Pancreatitis Is a Risk Factor for Pancreatic Cancer, and Incidence Increases With Duration of Disease: A Systematic Review and Meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There is an increased risk of PDAC in patients with CP, and incidence rates increase with CP disease duration."
    explanation: >-
      The human counterpart of the mouse result, with risk rising as the inflammation
      persists. PARTIAL because it measures cancer incidence in inflamed pancreata
      rather than anything at this node itself.
- name: Acinar-to-Ductal Metaplasia
  description: >-
    Differentiated acinar cells transdifferentiate into ductal-like cells. This is the
    predominant form of pancreatic ductal metaplasia and the cellular state in which
    PanIN lesions arise, which places the origin of PDAC in the acinar compartment
    rather than in pre-existing ducts despite the tumour's ductal histology.
  biological_scale: CELLULAR
  role: mediator
  cell_types:
  - preferred_term: pancreatic acinar cell
    term:
      id: CL:0002064
      label: pancreatic acinar cell
  - preferred_term: pancreatic ductal cell
    term:
      id: CL:0002079
      label: pancreatic ductal cell
  biological_processes:
  - preferred_term: transdifferentiation
    modifier: INCREASED
    term:
      id: GO:0060290
      label: transdifferentiation
  downstream:
  - target: Tumor Suppressor Inactivation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Metaplastic ducts give rise to PanIN lesions, which accumulate CDKN2A, TP53 and
      SMAD4 loss as they progress from low to high grade. The PanIN stage itself is the
      known intervening step and is not a separate node in this entry.
    evidence:
    - reference: PMID:35176433
      reference_title: Ductal metaplasia in pancreas.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The development of PDM to atypical hyperplasia is an important risk factor for pancreatic precursors, including intraepithelial neoplasia (PanIN), and pancreatic ductal adenocarcinoma (PDAC)."
      explanation: >-
        Places ductal metaplasia upstream of PanIN and PDAC. PARTIAL because the review
        reaches the precursor lesions rather than the tumour-suppressor losses this
        edge's target models.
  evidence:
  - reference: PMID:35176433
    reference_title: Ductal metaplasia in pancreas.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Acinar to ductal metaplasia (ADM) is the predominant form of ductal metaplasia in pancreas."
    explanation: >-
      Establishes ADM as the dominant metaplastic route in this organ, which is what
      this node models.
  - reference: PMID:17349585
    reference_title: Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "suggesting that PDA originates by differentiation of acinar/centroacinar cells or their precursors into ductal-like cells"
    explanation: >-
      Lineage evidence that the ductal-like cells of PDAC descend from the acinar
      compartment, which is the transdifferentiation this node annotates.
- name: KRAS Oncogene Activation
  conforms_to: "sustaining_proliferative_signaling#Constitutive Mitogenic Pathway Activation"
  description: >-
    Activating mutations in KRAS (predominantly G12D, G12V, G12R) occur in approximately
    90% of PDAC and are considered the initiating oncogenic event. Mutant KRAS is
    constitutively GTP-bound, driving aberrant activation of RAF-MEK-ERK and
    PI3K-AKT-mTOR signaling cascades that promote cell proliferation, survival,
    and metabolic reprogramming.
  evidence:
  - reference: PMID:35302596
    reference_title: Molecular Characterization of KRAS Wild-type Tumors in Patients with Pancreatic Adenocarcinoma.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: KRAS mutation (MT) is a major oncogenic driver in pancreatic ductal adenocarcinoma (PDAC).
    explanation: This directly supports KRAS as the central driver pathway in PDAC.
  - reference: DOI:10.3389/fmed.2024.1369136
    reference_title: "Targeting KRAS mutations in pancreatic cancer: opportunities for future strategies"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the case of pancreatic ductal adenocarcinomas (PDAC), 90-92% harbor mutations
      in the oncogene KRAS, triggering canonical MAPK signaling.
    explanation: >-
      This review confirms that 90-92% of PDAC harbor KRAS mutations that trigger
      canonical MAPK signaling, supporting the central role of KRAS in PDAC pathogenesis.
  - reference: DOI:10.1093/carcin/bgae064
    reference_title: "From precursor to cancer: decoding the intrinsic and extrinsic pathways of pancreatic intraepithelial neoplasia progression"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PanIN development begins with Kirsten rat sarcoma viral oncogene (KRAS) mutations
      driving PanIN initiation. Key additional mutations in cyclin-dependent kinase
      inhibitor 2A (CDKN2A), tumor protein p53 (TP53), and mothers against decapentaplegic
      homolog 4 (SMAD4) disrupt cell cycle control and genomic stability, crucial for
      PanIN progression from low-grade to high-grade dysplasia.
    explanation: >-
      This review confirms KRAS mutations as the initiating event in PanIN development,
      with additional tumor suppressor losses driving progression to invasive carcinoma.
  cell_types:
  - preferred_term: pancreatic ductal cell
    term:
      id: CL:0002079
      label: pancreatic ductal cell
  biological_processes:
  - preferred_term: MAPK cascade
    modifier: INCREASED
    term:
      id: GO:0000165
      label: MAPK cascade
  - preferred_term: phosphatidylinositol 3-kinase signaling
    modifier: INCREASED
    term:
      id: GO:0043491
      label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  downstream:
  - target: Immunosuppressive TME Reversibility under RAS(ON) Inhibition
    description: >-
      Because the immunosuppressive microenvironment is maintained by oncogenic KRAS
      signalling, inhibiting it reverses the myeloid and T-cell programs curated on
      the nodes downstream of this one.
  - target: Acquired RAS(ON) Inhibitor Resistance
    description: >-
      The same KRAS dependence that RAS(ON) multiselective inhibitors exploit is the
      node on which the acquired-resistance mechanisms curated here converge.
  - target: Early Dissemination and EMT
    description: >-
      The initiating KRAS lesion also licenses the cellular plasticity and EMT-like
      transitions through which PDAC cells disseminate before the primary tumour
      becomes clinically dominant.
  - target: Acinar-to-Ductal Metaplasia
    causal_link_type: DIRECT
    description: >-
      Mutant KRAS expressed in the acinar/centroacinar lineage drives those cells into
      the ductal-like state, so the metaplasia node is downstream of the oncogene as
      well as of the inflammation. Both inputs are required in the adult pancreas.
    evidence:
    - reference: PMID:17349585
      reference_title: Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We report that selective expression of an endogenous K-Ras(G12V) oncogene in embryonic cells of acinar/centroacinar lineage results in pancreatic intraepithelial neoplasias (PanINs) and invasive PDA, suggesting that PDA originates by differentiation of acinar/centroacinar cells or their precursors into ductal-like cells."
      explanation: >-
        Quoted through the trailing clause so the edge is self-evidencing: the same
        sentence carries both the acinar-lineage KRAS result and the inference that
        the tumour arises by differentiation into ductal-like cells, which is the
        metaplasia this edge targets.
  - target: Tumor Suppressor Inactivation
    description: KRAS activation cooperates with loss of tumor suppressors for full malignant transformation
    evidence:
    - reference: PMID:28810144
      reference_title: "Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS,
        TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS, RREB1, and PBRM1.
      explanation: >-
        The TCGA integrated genomic analysis confirmed co-occurrence of KRAS mutations
        with tumor suppressor inactivation (TP53, CDKN2A, SMAD4) in PDAC.
- name: Tumor Suppressor Inactivation
  conforms_to: "evading_growth_suppressors#Tumor Suppressor Inactivation"
  description: >-
    Progressive inactivation of key tumor suppressors drives PDAC progression. TP53
    mutations (~75%) disable DNA damage checkpoints and apoptosis. CDKN2A loss (~90%)
    removes cell cycle inhibition via p16INK4a. SMAD4 inactivation (~55%) disrupts
    TGF-beta tumor-suppressive signaling. These losses cooperate with KRAS activation
    to enable genomic instability and malignant transformation.
  evidence:
  - reference: PMID:18772397
    reference_title: "Core signaling pathways in human pancreatic cancers revealed by global genomic analyses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This list includes the classic tumor suppressor genes CDKN2A (p16), SMAD4,
      and TP53, as well as genes that had not previously been implicated in pancreatic
      cancer development.
    explanation: >-
      The landmark Jones et al. genomic analysis identified CDKN2A, SMAD4, and TP53 as
      core tumor suppressor genes in pancreatic cancer through global sequencing of 24
      advanced pancreatic adenocarcinomas.
  biological_processes:
  - preferred_term: regulation of cell cycle
    modifier: ABNORMAL
    term:
      id: GO:0051726
      label: regulation of cell cycle
  - preferred_term: apoptotic process
    modifier: DECREASED
    term:
      id: GO:0006915
      label: apoptotic process
  - preferred_term: DNA damage response
    modifier: ABNORMAL
    term:
      id: GO:0006974
      label: DNA damage response
  downstream:
  - target: Desmoplastic Stroma
    description: Genomic instability and tumor-stroma crosstalk promote desmoplasia
    evidence:
    - reference: PMID:30366930
      reference_title: "IL1-Induced JAK/STAT Signaling Is Antagonized by TGFβ to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Within the stroma, cancer-associated fibroblasts (CAF) secrete tropic factors
        and extracellular matrix components, and have been implicated in PDAC
        progression and chemotherapy resistance.
      explanation: >-
        Biffi et al. demonstrated that tumor-secreted ligands TGF-beta and IL1 drive
        CAF heterogeneity and desmoplastic stroma formation in PDAC.
  - target: Extracellular Vesicle-Mediated Immune Escape
    description: Transformed PDAC cells release functionally active exosomes that condition host tissue ahead of metastasis
    evidence:
    - reference: PMID:25985394
      reference_title: "Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Here, we show that PDAC-derived exosomes induce liver pre-metastatic niche
        formation in naive mice and consequently increase liver metastatic burden.
      explanation: >-
        Establishes that exosomes released by transformed PDAC cells are functionally
        active on host tissue, wiring EV secretion downstream of malignant transformation
        rather than leaving it as a disconnected source node.
- name: Desmoplastic Stroma
  description: >-
    PDAC is characterized by a dense desmoplastic stroma comprising up to 80% of tumor
    mass. Pancreatic stellate cells (PSCs) are activated by tumor-derived signals
    (TGF-beta, PDGF, sonic hedgehog) and differentiate into myofibroblasts that
    deposit abundant extracellular matrix including collagen and hyaluronan. This
    stroma creates high interstitial pressure, impairs drug delivery, promotes
    immune exclusion, and provides survival signals to tumor cells.
  evidence:
  - reference: DOI:10.3390/cancers16162876
    reference_title: "Precision Targeting Strategies in Pancreatic Cancer: The Role of Tumor Microenvironment"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cells of the tumor microenvironment (TME) interact with cancer cells in pancreatic
      ductal adenocarcinoma (PDAC) tumors to preserve cancer cells' metabolism, inhibit
      drug delivery, enhance immune suppression mechanisms and finally develop resistance
      to chemotherapy and immunotherapy.
    explanation: >-
      This review confirms that the PDAC TME inhibits drug delivery and enhances immune
      suppression, consistent with the role of the desmoplastic stroma in treatment
      resistance.
  - reference: DOI:10.1146/annurev-pathmechdis-031621-024600
    reference_title: "Tumor Microenvironment in Pancreatic Cancer Pathogenesis and Therapeutic Resistance"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pancreatic ductal adenocarcinoma (PDAC) features a prominent stromal microenvironment
      with remarkable cellular and spatial heterogeneity that meaningfully impacts disease
      biology and treatment resistance.
    explanation: >-
      This review describes the prominent stromal microenvironment in PDAC and its role
      in treatment resistance, supporting the desmoplastic stroma mechanism.
  cell_types:
  - preferred_term: pancreatic stellate cell
    term:
      id: CL:0002410
      label: pancreatic stellate cell
  biological_processes:
  - preferred_term: extracellular matrix organization
    modifier: INCREASED
    term:
      id: GO:0030198
      label: extracellular matrix organization
  - preferred_term: collagen biosynthetic process
    modifier: INCREASED
    term:
      id: GO:0032964
      label: collagen biosynthetic process
  downstream:
  - target: CAF-Mediated T Cell Exclusion
    description: Activated fibroblast states and ECM-rich niches spatially exclude effector T cells and reinforce immune suppression
- name: CAF-Mediated T Cell Exclusion
  description: >-
    Distinct cancer-associated fibroblast states within PDAC stroma secrete extracellular
    matrix and chemokine programs that trap or exclude effector T cells from tumor nests.
    This stromal immune exclusion helps explain the poor activity of checkpoint blockade
    in unselected PDAC and is a natural mechanistic bridge between desmoplasia and
    immune escape.
  cell_types:
  - preferred_term: pancreatic stellate cell
    term:
      id: CL:0002410
      label: pancreatic stellate cell
  - preferred_term: CD8-positive, alpha-beta T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: chemokine-mediated signaling pathway
    modifier: INCREASED
    term:
      id: GO:0070098
      label: chemokine-mediated signaling pathway
  - preferred_term: Negative Regulation of T Cell Mediated Immunity
    modifier: INCREASED
    term:
      id: GO:0002710
      label: negative regulation of T cell mediated immunity
  downstream:
  - target: Immune Evasion
    description: Stromal chemokines and fibroblast-rich exclusion zones reduce effective anti-tumor T cell contact with malignant glands
- name: Extracellular Vesicle-Mediated Immune Escape
  biological_scale: CELLULAR
  description: >-
    PDAC tumor cells secrete extracellular vesicles (exosomes and microvesicles) carrying
    immunomodulatory molecules and tumor-associated signals. The experimentally resolved
    arm of this mechanism is myeloid: PDAC-derived exosomes are taken up by resident
    tissue macrophages (Kupffer cells), which respond by secreting TGF-beta and
    establishing a fibrotic microenvironment that recruits further bone marrow-derived
    macrophages. The exosomal cargo protein macrophage migration inhibitory factor (MIF)
    is required for this reprogramming — blocking it prevents niche formation and
    metastasis — identifying EV cargo transfer as a causal, not merely correlative,
    route by which PDAC conditions host tissue in favor of tumor progression.
  notes: >-
    Deliberately scoped to the macrophage arm. EV-mediated suppression of dendritic cell
    antigen presentation, T cell exhaustion, and microRNA cargo transfer are widely
    proposed for PDAC but are not curated here because no PDAC-specific primary
    experimental evidence was found to support them; the sole EV reference originally
    cited (PPR:PPR1285314) states only the generic "immunomodulatory molecules" framing
    as background, and its own contribution is in-silico candidate prioritization.
  evidence:
  - reference: PMID:25985394
    reference_title: "Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Uptake of PDAC-derived exosomes by Kupffer cells caused transforming growth factor
      β secretion and upregulation of fibronectin production by hepatic stellate cells.
      This fibrotic microenvironment enhanced recruitment of bone marrow-derived
      macrophages.
    explanation: >-
      Primary experimental evidence that PDAC-derived exosomes are taken up by resident
      macrophages and reprogram them, supporting the macrophage cell-type annotation and
      the TGF-beta production process on this node.
  - reference: PMID:25985394
    reference_title: "Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We found that macrophage migration inhibitory factor (MIF) was highly expressed in
      PDAC-derived exosomes, and its blockade prevented liver pre-metastatic niche
      formation and metastasis.
    explanation: >-
      Loss-of-function evidence that a specific exosomal cargo protein is causally
      required, establishing EV cargo transfer rather than mere EV presence as the
      operative mechanism.
  - reference: PPR:PPR1285314
    reference_title: "A dual-layer computational framework for prioritising therapeutic candidates targeting extracellular vesicle-mediated immune escape in pancreatic ductal adenocarcinoma"
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Tumour-derived extracellular vesicles (EVs) contribute to PDAC progression by
      transferring immunomodulatory molecules and tumour-associated signals, suggesting
      EV-associated processes as potential intervention opportunities.
    explanation: >-
      Cited only for the general framing that tumor-derived EVs transfer immunomodulatory
      cargo in PDAC. This is the preprint's background statement, not its finding — its
      own contribution is computational candidate prioritization — so it is retained as
      corroborating context alongside, not in place of, the primary evidence above.
  cell_types:
  - preferred_term: pancreatic ductal cell
    term:
      id: CL:0002079
      label: pancreatic ductal cell
  - preferred_term: Kupffer cell
    term:
      id: CL:0000091
      label: Kupffer cell
  - preferred_term: recruited bone marrow-derived macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: extracellular exosome biogenesis
    modifier: INCREASED
    term:
      id: GO:0097734
      label: extracellular exosome biogenesis
  - preferred_term: transforming growth factor beta production
    modifier: INCREASED
    term:
      id: GO:0071604
      label: transforming growth factor beta production
  downstream:
  - target: Immune Evasion
    description: EV-delivered cargo reprograms resident and recruited macrophages toward the immunosuppressive myeloid compartment that characterizes the PDAC microenvironment
- name: Immune Evasion
  description: >-
    PDAC creates a profoundly immunosuppressive tumor microenvironment. The desmoplastic
    stroma physically excludes cytotoxic T cells. Regulatory T cells, myeloid-derived
    suppressor cells, and tumor-associated macrophages accumulate and suppress
    anti-tumor immunity. PDAC tumors also exhibit low mutational burden and poor
    neoantigen presentation, contributing to resistance to immunotherapy.
  evidence:
  - reference: DOI:10.1186/s12943-023-01813-y
    reference_title: "Molecular and metabolic regulation of immunosuppression in metastatic pancreatic ductal adenocarcinoma"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunosuppression is a hallmark of pancreatic ductal adenocarcinoma (PDAC),
      contributing to early metastasis and poor patient survival.
    explanation: >-
      This review establishes immunosuppression as a hallmark of PDAC that contributes
      to metastasis and poor survival, supporting the immune evasion mechanism.
  - reference: DOI:10.1186/s12943-023-01813-y
    reference_title: "Molecular and metabolic regulation of immunosuppression in metastatic pancreatic ductal adenocarcinoma"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Following chemokine and exosomal guidance, these cells metastasize to the
      organ-specific pre-metastatic niches (PMNs) constituted by local resident cells,
      stromal fibroblasts, and suppressive immune cells, such as the metastasis-associated
      macrophages, neutrophils, and myeloid-derived suppressor cells.
    explanation: >-
      This describes the immune cell populations in PDAC metastatic niches including
      macrophages, neutrophils, and MDSCs that constitute the immunosuppressive
      microenvironment.
  cell_types:
  - preferred_term: regulatory T cell
    term:
      id: CL:0000815
      label: regulatory T cell
  - preferred_term: tumor-associated macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: immune response
    modifier: DECREASED
    term:
      id: GO:0006955
      label: immune response
- name: Early Dissemination and EMT
  conforms_to: "invasion_and_metastasis#Epithelial-Mesenchymal Transition Activation"
  description: >-
    Metastatic spread can begin early, before the primary tumor becomes clinically
    dominant.
    Cellular plasticity, EMT-like transitions, and squamous or mesenchymal programs
    enable
    escape from precursor and invasive lesions.
  evidence:
  - reference: PMID:41814069
    reference_title: Early cellular plasticity promotes progression and dissemination in pancreatic adenocarcinoma.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: We explore the biological and spatial-temporal evolution of precancerous lesions, such as PanINs and IPMNs, and examine how phenotypic plasticity and overlapping cellular programs-including squamous transdifferentiation, epithelial-to-mesenchymal transition (EMT), and acquisition of mesenchymal features-contribute to early dissemination, treatment resistance, and surgical failure.
    explanation: This directly supports EMT-linked early dissemination in pancreatic adenocarcinoma.
  biological_processes:
  - preferred_term: epithelial to mesenchymal transition
    modifier: INCREASED
    term:
      id: GO:0001837
      label: epithelial to mesenchymal transition
  - preferred_term: cell migration
    modifier: INCREASED
    term:
      id: GO:0016477
      label: cell migration
  downstream:
  - target: Perineural Invasion
    description: >-
      Invasive, plastic tumour cells track along intrapancreatic nerves, using
      neural routes as low-resistance conduits for local and regional spread.
- name: Perineural Invasion
  description: >-
    Pancreatic adenocarcinoma has marked neurotropism. Tumor cells track along nerves,
    exploit neurotrophic cues, and use neural routes as low-resistance corridors for
    local
    spread and distant metastatic behavior.
  evidence:
  - reference: PMID:35449152
    reference_title: HGF/c-Met pathway facilitates the perineural invasion of pancreatic cancer by activating the mTOR/NGF axis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Perineural invasion (PNI) is a pathologic feature of pancreatic cancer and is associated with poor outcomes, metastasis, and recurrence in pancreatic cancer patients.
    explanation: This supports perineural invasion as a metastasis-associated feature of pancreatic cancer.
  biological_processes:
  - preferred_term: positive regulation of cell migration
    modifier: INCREASED
    term:
      id: GO:0030335
      label: positive regulation of cell migration
- name: Cyclophilin A Loss and Reduced Tri-Complex Engagement
  biological_scale: MOLECULAR
  description: >-
    Under daraxonrasib (RMC-6236) pressure, downregulation of cyclophilin A
    (PPIA) - the intracellular chaperone the drug must bind to assemble the
    RAS(ON)-engaging tri-complex - reduces on-target drug engagement while
    RAS-GTP signaling is retained. This is a drug-class-specific,
    KRAS-G12D-associated route of acquired resistance to tri-complex RAS(ON)
    inhibitors.
  genes:
  - preferred_term: PPIA
    term:
      id: hgnc:9253
      label: PPIA
  molecular_functions:
  - preferred_term: peptidyl-prolyl cis-trans isomerase activity
    modifier: DECREASED
    term:
      id: GO:0003755
      label: peptidyl-prolyl cis-trans isomerase activity
  evidence:
  - reference: PMID:42465401
    reference_title: 'Overcoming Daraxonrasib Resistance: Allele-Specific Mechanisms Guide Salvage Therapy in Pancreatic Cancer.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: In contrast, KRAS G12D resistance arose through retained KRAS G12D -GTP signaling, with a decrease of cyclophilin A (CypA) protein, the binding partner required for daraxonrasib activity.
    explanation: >-
      Identifies CypA (PPIA) downregulation as a daraxonrasib-specific resistance
      route in KRAS-G12D PDAC, reducing tri-complex formation while RAS-GTP
      signaling persists.
  downstream:
  - target: Acquired RAS(ON) Inhibitor Resistance
    description: Reduced tri-complex engagement lets RAS-GTP signaling and proliferation resume despite continued dosing.
    causal_link_type: DIRECT
    hypothesis_groups:
    - ras_on_inhibitor_acquired_resistance
- name: RAS-Independent Cell-Cycle Uncoupling
  biological_scale: CELLULAR
  description: >-
    A RAS-independent escape in which cell-cycle progression becomes uncoupled
    from RAS-MAPK output, so tumor cells continue proliferating despite
    multiselective RAS(ON) inhibition. Co-targeting the cell-cycle kinases
    CDK4/6 and CDK2 restores sensitivity; this transcriptional/cell-cycle class
    of resistance is not reversed by deeper RAS inhibition alone.
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  evidence:
  - reference: PMID:41959066
    reference_title: Targeting Distinct Cell Cycle Nodes Overcomes KRAS/RAS Inhibitor Resistance.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: While these pathways can be broadly inhibited using the pan-RAS-ON inhibitor RMC-6236, cells remained capable of developing acquired resistance where cell proliferation is uncoupled from RAS signaling.
    explanation: >-
      Establishes RAS-independent cell-cycle continuation under daraxonrasib
      (RMC-6236) as a resistance route restorable by CDK4/6 and CDK2 co-targeting.
  downstream:
  - target: Acquired RAS(ON) Inhibitor Resistance
    description: Proliferation decoupled from RAS sustains tumor growth under continued RAS(ON) inhibition.
    causal_link_type: DIRECT
    hypothesis_groups:
    - ras_on_inhibitor_acquired_resistance
- name: Acquired RAS(ON) Inhibitor Resistance
  biological_scale: CELLULAR
  description: >-
    Convergent outcome node: tumor regrowth under daraxonrasib after an initial
    response, reflected clinically in the finite progression-free survival
    observed in RASolute 302. Multiple upstream routes converge here - cyclophilin
    A loss, RAS-independent cell-cycle uncoupling, RTK/feedback and on-target RAS
    reactivation, and mTOR/JUN-AP1 hyperactivation; which route dominates in
    patients is unresolved (no longitudinal daraxonrasib resistance dataset yet).
  evidence:
  - reference: PMID:42223072
    reference_title: Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The median progression-free survival in the RAS G12 population was 7.3 months with daraxonrasib and 3.5 months with chemotherapy, and that in the overall population was 7.2 months and 3.6 months, respectively; the hazard ratios were 0.45 and 0.49, respectively (P<0.001 for both comparisons).
    explanation: >-
      The finite progression-free survival on daraxonrasib is the clinical
      readout of the acquired resistance that the upstream routes converge on.
- name: On-Target RAS Reactivation and KRAS Amplification
  biological_scale: MOLECULAR
  description: >-
    Restoration of RAS-GTP above the inhibition threshold via KRAS amplification
    or a secondary/second-site RAS mutation. Because multiselective RAS(ON)
    inhibitors suppress mutant and wild-type RAS, many such routes often remain
    targetable by deeper engagement, so amplification must raise the threshold
    substantially to drive durable escape.
  evidence:
  - reference: PMID:41165456
    reference_title: RAS-GTP Inhibition Overcomes Acquired Resistance to KRASG12C Inhibitors Mediated by Oncogenic and Wild-Type RAS Activation in Non-Small Cell Lung Cancer.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Two models reactivated RAS signaling, either via KRASG12C gene amplification or NRASG13R mutation, and were vulnerable to dual inhibition by RAS(ON) G12C-selective and RAS(ON) multiselective inhibitors, RMC-4998 and RMC-7977.
    explanation: >-
      Supported in NSCLC models (tool analog RMC-7977) and inferred for
      PDAC/daraxonrasib; PARTIAL because these RAS-reactivating routes often
      remained sensitive to multiselective RAS(ON) inhibition.
  downstream:
  - target: Acquired RAS(ON) Inhibitor Resistance
    description: Raised RAS-GTP restores mitogenic signaling despite continued dosing.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - ras_on_inhibitor_acquired_resistance
- name: RTK and Feedback Pathway Reactivation
  biological_scale: MOLECULAR
  description: >-
    Relief of ERK-mediated negative feedback reactivates receptor tyrosine
    kinases and adaptors (EGFR/ERBB, AXL/PDGFR, SHP2, FAK, YAP-SDC1), restoring
    RAS-GTP/ERK output or providing RAS-parallel survival signaling. Best
    demonstrated against partial (MEK/G12C) blockade; its sufficiency against
    complete RAS(ON) suppression is uncertain.
  evidence:
  - reference: PMID:41165456
    reference_title: RAS-GTP Inhibition Overcomes Acquired Resistance to KRASG12C Inhibitors Mediated by Oncogenic and Wild-Type RAS Activation in Non-Small Cell Lung Cancer.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Two models, which lacked any discernable genomic alteration, acquired resistance associated with increased receptor tyrosine kinase activity and downstream persistent RAS activity and were sensitive to RAS-GTP inhibition by RMC-7977.
    explanation: >-
      RTK-driven persistent RAS activity mediated G12C-inhibitor resistance but
      remained sensitive to multiselective RAS(ON) inhibition; PARTIAL and
      context is NSCLC, so sufficiency against complete RAS(ON) block in PDAC is
      an open question.
  downstream:
  - target: Acquired RAS(ON) Inhibitor Resistance
    description: RTK-driven signaling restores proliferation or parallel survival under inhibition.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - ras_on_inhibitor_acquired_resistance
- name: Adaptive mTOR and JUN-AP1 Transcriptional Program
  biological_scale: CELLULAR
  description: >-
    Convergent adaptive-transcriptional escape in which mTOR and JUN/AP-1
    hyperactivation overcome MAPK suppression; JUN is the most downstream
    mediator and is indirectly targetable via MAP2K4 inhibition.
  evidence:
  - reference: PMID:41572361
    reference_title: CRISPR knockout screens reveal JUN as the master mediator of resistance to MAPK inhibition in KRAS-mutant pancreatic cancer.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Through unbiased CRISPR-based screenings, we identified mTOR and JUN hyperactivation as interconnected mechanisms that overcome MAPK suppression.
    explanation: >-
      PDAC CRISPR screens (explicitly anticipating RAS(ON) multi-selective
      inhibitor resistance) identify the mTOR/JUN-AP1 hub as an adaptive
      transcriptional escape.
  downstream:
  - target: Acquired RAS(ON) Inhibitor Resistance
    description: mTOR/JUN-AP1 output restores proliferation independent of restored RAS-GTP.
    causal_link_type: DIRECT
    hypothesis_groups:
    - ras_on_inhibitor_acquired_resistance
- name: Mitochondrial Remodeling and Ferroptosis Vulnerability
  biological_scale: CELLULAR
  description: >-
    Profound RAS-MAPK suppression drives persistent mitochondrial remodeling and
    a lipid-peroxidase/ROS dependency, creating a subtype-independent ferroptosis
    (GPX4) vulnerability in the resistant state - a salvage target rather than a
    growth-restoring route.
  biological_processes:
  - preferred_term: ferroptosis
    modifier: INCREASED
    term:
      id: GO:0097707
      label: ferroptosis
  evidence:
  - reference: PMID:41545339
    reference_title: Vertical RAS pathway inhibition in pancreatic cancer drives therapeutically exploitable mitochondrial alterations.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We found that dual SHP2/mitogen-activated protein kinase kinase (MEK1/2) inhibition induces major alterations in mitochondrial mass and function, impacts reactive oxygen species (ROS) homeostasis and triggers lipid peroxidase dependency.
    explanation: >-
      Vertical/direct RAS-pathway inhibition in PDAC induces a persistent
      mitochondrial-remodeled, ferroptosis-vulnerable resistant state - an
      actionable metabolic dependency of the resistant tumor.
  downstream:
  - target: Acquired RAS(ON) Inhibitor Resistance
    description: The mitochondrial-remodeled state accompanies therapy resistance and defines a ferroptosis salvage vulnerability.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - ras_on_inhibitor_acquired_resistance
- name: MYC Amplification-Driven RAS-Independent Proliferation
  biological_scale: MOLECULAR
  description: >-
    Amplification of the downstream transcriptional effector MYC is proposed to
    restore proliferation independent of RAS engagement, a RAS-independent route
    not reversed by deeper RAS inhibition. Evidence is currently review-level and
    needs primary, drug-matched confirmation.
  evidence:
  - reference: PMID:39586491
    reference_title: Breakthrough in RAS targeting with pan-RAS(ON) inhibitors RMC-7977 and RMC-6236.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: MYC amplification was reported to be a main contributor to the development of resistance.
    explanation: >-
      WEAK / review-level: a focused review synthesizing preclinical studies
      names MYC amplification as a main resistance contributor to multiselective
      tri-complex RAS(ON) inhibitors; primary drug-matched PDAC data are needed.
  downstream:
  - target: Acquired RAS(ON) Inhibitor Resistance
    description: MYC-driven proliferation bypasses RAS dependence.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - ras_on_inhibitor_acquired_resistance
- name: Immunosuppressive TME Reversibility under RAS(ON) Inhibition
  biological_scale: TISSUE
  description: >-
    Mechanism node for the immune-remodeling hypothesis: the immunosuppressive,
    T-cell-excluded microenvironment of PDAC is substantially
    RAS-activity-dependent and partially reversible by RAS-pathway inhibition,
    which promotes
    effector immune infiltration but requires checkpoint-blockade combination for
    durable regression. Daraxonrasib-specific PDAC immune data are still limited
    (strongest data use the G12D-selective MRTX1133).
  evidence:
  - reference: PMID:37782788
    reference_title: Oncogenic dependency plays a dominant role in the immune response to cancer.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Lowering KRAS activity in established tumors promotes immune infiltration, but with a limited antitumor effect, whereas combining KRAS/MEK inhibition with immune checkpoint blockade achieves durable regression in preclinical models.
    explanation: >-
      Establishes that the tumor immune composition tracks RAS activity and that
      RAS-pathway inhibition remodels it but needs checkpoint-blockade
      combination for durable benefit.
- name: Myeloid Suppression Relief and CD8 Effector Infiltration
  biological_scale: TISSUE
  description: >-
    RAS-pathway inhibition decreases intratumoral myeloid infiltration, increases
    CD8+ effector T cells, and reprograms cancer-associated fibroblasts.
    Demonstrated with the G12D-selective MRTX1133 rather than daraxonrasib.
  cell_types:
  - preferred_term: CD8-positive effector T cell
    modifier: INCREASED
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  evidence:
  - reference: PMID:37625401
    reference_title: KRAS(G12D) inhibition reprograms the microenvironment of early and advanced pancreatic cancer to promote FAS-mediated killing by CD8(+) T cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Employing 16 different models of KRASG12D-driven PDAC, we demonstrate that MRTX1133 reverses early PDAC growth, increases intratumoral CD8+ effector T cells, decreases myeloid infiltration, and reprograms cancer-associated fibroblasts.
    explanation: >-
      Strong PDAC-model support for myeloid relief and CD8 effector infiltration;
      PARTIAL because it is achieved with the G12D-selective MRTX1133, not
      multiselective daraxonrasib.
  downstream:
  - target: Immunosuppressive TME Reversibility under RAS(ON) Inhibition
    description: Relief of myeloid suppression and CD8 infiltration are components of the RAS-dependent immune reversal.
    causal_link_type: DIRECT
    hypothesis_groups:
    - ras_on_inhibition_immune_tme_remodeling
- name: Tumor-Cell FAS Induction and CD8-Mediated Killing
  biological_scale: CELLULAR
  description: >-
    RAS/KRAS-G12D inhibition induces tumor-cell FAS, enabling CD8+ T-cell-mediated
    killing; regression of advanced PDAC requires CD8+ T cells and synergizes with
    checkpoint blockade (preclinical, MRTX1133).
  evidence:
  - reference: PMID:36824971
    reference_title: Oncogenic Kras (G12D) specific non-covalent inhibitor reprograms tumor microenvironment to prevent and reverse early pre-neoplastic pancreatic lesions and in combination with immunotherapy regresses advanced PDAC in a CD8 (+) T cells dependent manner.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Regression of advanced PDAC requires CD8 + T cells and immune checkpoint blockade therapy (iCBT) synergizes with MRTX1133 to eradicate PDAC and prolong overall survival.
    explanation: >-
      CD8-dependent, checkpoint-synergistic regression on RAS-G12D inhibition;
      PARTIAL because the agent is the G12D-selective MRTX1133, not daraxonrasib.
  downstream:
  - target: Immunosuppressive TME Reversibility under RAS(ON) Inhibition
    description: FAS-enabled CD8 killing is an effector arm of the RAS-dependent immune reversal.
    causal_link_type: DIRECT
    hypothesis_groups:
    - ras_on_inhibition_immune_tme_remodeling
- name: Antigen Presentation Restoration
  biological_scale: CELLULAR
  description: >-
    Proposed increase in tumor antigen presentation on RAS(ON) inhibition. WEAK
    and competing for PDAC: MHC-I/antigen presentation in PDAC is largely
    autophagy(NBR1)- and FAK-controlled and only weakly RAS-owned; the direct
    daraxonrasib evidence is in NSCLC, not PDAC.
  biological_processes:
  - preferred_term: antigen processing and presentation
    modifier: INCREASED
    term:
      id: GO:0019882
      label: antigen processing and presentation
  evidence:
  - reference: PMID:41670434
    reference_title: Abrogation of Oncogenic RAS Signaling by a RAS(ON) Inhibitor Doublet Primes Immune-Refractory KRASG12C-Mutant NSCLC for Immune Checkpoint Blockade.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: in immune-competent preclinical models, the RAS(ON) inhibitor doublet enhances tumor immune recognition by boosting antigen presentation and remodeling the suppressive tumor microenvironment, thus promoting immune-dependent complete regressions and sensitization of an immunorefractory model to checkpoint blockade.
    explanation: >-
      WEAK / competing for PDAC: the daraxonrasib-containing evidence for boosted
      antigen presentation is in KRAS-G12C NSCLC; in PDAC, MHC-I is dominantly
      autophagy(NBR1)/FAK-controlled and largely RAS-independent.
  downstream:
  - target: Immunosuppressive TME Reversibility under RAS(ON) Inhibition
    description: A weakly RAS-owned, competing contribution to immune reversal.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - ras_on_inhibition_immune_tme_remodeling
- name: Regulatory T-Cell Relief
  biological_scale: TISSUE
  description: >-
    Proposed relief of regulatory-T-cell dominance on RAS/daraxonrasib
    inhibition. UNSUPPORTED source absence: a targeted literature search found no
    primary evidence that RAS or daraxonrasib inhibition depletes or disarms
    Tregs in PDAC. Retained here as an explicitly unverified edge for the
    immune-remodeling hypothesis, pending direct Treg profiling.
  cell_types:
  - preferred_term: regulatory T cell
    term:
      id: CL:0000815
      label: regulatory T cell
  downstream:
  - target: Immunosuppressive TME Reversibility under RAS(ON) Inhibition
    description: Proposed but currently unsupported contribution (source absence); no primary PDAC evidence found.
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - ras_on_inhibition_immune_tme_remodeling
- name: USP20 Cholesterol-Metabolism CD8 Exhaustion Checkpoint
  biological_scale: CELLULAR
  description: >-
    KRAS-G12D upregulates USP20 (via EGR1) to drive cholesterol metabolism and
    CD8+ T-cell exhaustion; RAS inhibition reverses this exhaustion axis but
    triggers compensatory ULK1 autophagy, so co-targeting cholesterol metabolism
    and autophagy potentiates KRAS-inhibitor efficacy. Human-tissue-anchored.
  evidence:
  - reference: PMID:42392864
    reference_title: USP20 promotes CD8(+) T cell exhaustion and impairs KRAS(G12D) inhibitor efficacy by orchestrating cholesterol metabolism and autophagy in pancreatic cancer.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We found that KRASG12D enhanced cholesterol metabolism and promoted CD8+ T cell exhaustion, whereas KRASG12D inhibition or cholesterol synthesis blockade induced compensatory ULK1-associated autophagy.
    explanation: >-
      Adds a human-anchored metabolic-immune layer: KRAS drives a cholesterol/
      USP20-mediated CD8-exhaustion program reversed by RAS inhibition, with a
      compensatory autophagy escape that gates KRAS-inhibitor immune efficacy.
  downstream:
  - target: Immunosuppressive TME Reversibility under RAS(ON) Inhibition
    description: Reversal of the cholesterol-driven CD8-exhaustion program contributes to RAS-dependent immune reversal.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - ras_on_inhibition_immune_tme_remodeling
- name: CDK8-CXCL2 Adaptive Immune Reversal
  biological_scale: CELLULAR
  description: >-
    Durability-limiting counter-program: with long-term KRAS-G12D-inhibitor or
    daraxonrasib treatment, CDK8 remodels the microenvironment (CXCL2 chemokine
    secretion, FAS suppression) and reverses the initial immune gains, driving
    resistance. Bridges the immune-remodeling and resistance hypotheses.
  evidence:
  - reference: PMID:42436354
    reference_title: CDK8 remodels the tumor microenvironment and promotes resistance to KRAS(G12D) inhibitors and daraxonrasib in PDAC.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: long-term treatment results in reversal of the immune responses leading to resistance promoted by multiprotein mediator complex associated kinase CDK8.
    explanation: >-
      CDK8-driven reversal of the immune-remodeling window is a durability limit
      that converts the therapeutic immune response into a resistance driver;
      names daraxonrasib explicitly.
  downstream:
  - target: Acquired RAS(ON) Inhibitor Resistance
    description: CDK8-mediated reversal of immune remodeling drives adaptive resistance.
    causal_link_type: DIRECT
    hypothesis_groups:
    - ras_on_inhibition_immune_tme_remodeling
    - ras_on_inhibitor_acquired_resistance
histopathology:
- name: Pancreatic Ductal Adenocarcinoma
  finding_term:
    preferred_term: Pancreatic ductal adenocarcinoma
    term:
      id: NCIT:C9120
      label: Pancreatic Ductal Adenocarcinoma
  frequency: VERY_FREQUENT
  description: >-
    Malignant gland-forming ductal adenocarcinoma is the dominant histopathologic
    pattern in PDAC.
- name: Desmoplastic Stroma
  finding_term:
    preferred_term: desmoplastic stroma
    term:
      id: NCIT:C36178
      label: Fibrotic Stroma Formation
  frequency: VERY_FREQUENT
  description: >-
    Dense collagen-rich fibrotic stroma surrounding malignant glands is a defining
    histopathologic feature of PDAC.
phenotypes:
- category: Neoplastic
  name: Pancreatic Adenocarcinoma
  frequency: OBLIGATE
  description: >-
    PDAC presents as a malignant epithelial neoplasm of the pancreas with glandular
    differentiation arising from the ductal epithelium.
  evidence:
  - reference: PMID:32593337
    reference_title: "Pancreatic cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pancreatic cancer is a highly fatal disease with a 5-year survival rate of
      approximately 10% in the USA, and it is becoming an increasingly common cause
      of cancer mortality.
    explanation: >-
      The Lancet seminar confirms pancreatic cancer as a highly fatal malignancy
      with approximately 10% 5-year survival.
  phenotype_term:
    preferred_term: Pancreatic adenocarcinoma
    term:
      id: HP:0006725
      label: Pancreatic adenocarcinoma
- category: Clinical
  name: Abdominal Pain
  frequency: VERY_FREQUENT
  description: >-
    Epigastric or back pain is a common presenting symptom, often indicating
    retroperitoneal invasion or celiac plexus involvement.
  evidence:
  - reference: PMID:25726049
    reference_title: Diagnostic evaluation and staging of pancreatic ductal adenocarcinoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Common signs and symptoms of PDA include abdominal or back pain, jaundice, weight loss, pruritus, and nausea/vomiting.
    explanation: Directly lists abdominal pain as a common presenting symptom of pancreatic ductal adenocarcinoma.
  - reference: PMID:32593337
    reference_title: "Pancreatic cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients typically present with advanced disease due to lack of or vague
      symptoms when the cancer is still localised.
    explanation: >-
      The Lancet review notes that patients present with advanced disease due to
      vague early symptoms, consistent with abdominal pain as a common late presentation.
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
- category: Clinical
  name: Obstructive Jaundice
  frequency: FREQUENT
  description: >-
    Painless obstructive jaundice is a classic presentation for tumors in the
    pancreatic head, caused by compression of the common bile duct.
  phenotype_term:
    preferred_term: Obstructive jaundice
    term:
      id: HP:0001396
      label: Cholestasis
- category: Clinical
  name: Weight Loss
  frequency: VERY_FREQUENT
  description: >-
    Significant unintentional weight loss occurs in the majority of patients at
    diagnosis due to cancer cachexia and exocrine pancreatic insufficiency.
  evidence:
  - reference: PMID:28507210
    reference_title: "Diabetes, Pancreatogenic Diabetes, and Pancreatic Cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      most patients with PDAC report weight loss rather than weight gain. The
      clinical features of deteriorating glycemic control in conjunction with weight
      loss that accompanies PDAC prior to its diagnosis are atypical for T2DM
    explanation: >-
      Andersen et al. note that weight loss is a characteristic clinical feature of
      PDAC, distinguishing it from typical T2DM presentation.
  phenotype_term:
    preferred_term: Weight loss
    term:
      id: HP:0001824
      label: Weight loss
- category: Clinical
  name: New-Onset Diabetes
  frequency: FREQUENT
  description: >-
    New-onset diabetes mellitus within 2-3 years before PDAC diagnosis occurs in
    a substantial proportion of patients, likely reflecting tumor-induced
    metabolic derangement and beta-cell dysfunction.
  evidence:
  - reference: PMID:28507210
    reference_title: "Diabetes, Pancreatogenic Diabetes, and Pancreatic Cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The relationships between diabetes and pancreatic ductal adenocarcinoma (PDAC)
      are complex. Longstanding type 2 diabetes (T2DM) is a risk factor for pancreatic
      cancer, but increasing epidemiological data point to PDAC as also a cause of
      diabetes due to unknown mechanisms.
    explanation: >-
      Andersen et al. establish that PDAC causes new-onset diabetes through unknown
      mechanisms, demonstrating the bidirectional relationship between PDAC and diabetes.
  phenotype_term:
    preferred_term: Type II diabetes mellitus
    term:
      id: HP:0005978
      label: Type II diabetes mellitus
- category: Clinical
  name: Hepatic Metastases
  frequency: VERY_FREQUENT
  description: >-
    The liver is the most common site of distant metastasis in PDAC, present in
    the majority of patients with advanced disease.
  evidence:
  - reference: PMID:36776324
    reference_title: "A population-based study of synchronous distant metastases and prognosis in patients with PDAC at initial diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There was a highest incidence of liver metastases from pancreatic cancer
      (2387,74.36%), followed by lung (625,19.47%), bone (190,5.92%), and brain
      (8,0.25%).
    explanation: >-
      This population-based study of metastatic PDAC directly identifies liver
      metastases as the most common distant metastatic site at diagnosis.
  phenotype_term:
    preferred_term: Hepatic metastasis
    term:
      id: HP:0002896
      label: Neoplasm of the liver
- category: Constitutional
  name: Fatigue
  description: Fatigue reflects systemic inflammation, malnutrition, and treatment intensity.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
- category: Musculoskeletal
  name: Back pain
  frequency: FREQUENT
  description: Back pain reflects retroperitoneal spread and neural invasion.
  phenotype_term:
    preferred_term: Back pain
    term:
      id: HP:0003418
      label: Back pain
  evidence:
  - reference: PMID:25726049
    reference_title: Diagnostic evaluation and staging of pancreatic ductal adenocarcinoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common signs and symptoms of PDA include abdominal or back pain,
      jaundice, weight loss, pruritus, and nausea/vomiting.
    explanation: >-
      Directly lists back pain as a common presenting symptom of pancreatic
      ductal adenocarcinoma.
biochemical:
- name: CA 19-9
  evidence:
  - reference: PMID:23331006
    reference_title: "The clinical utility of CA 19-9 in pancreatic adenocarcinoma: diagnostic and prognostic updates."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 57 studies involving 3,285 pancreatic carcinoma cases, the combined
      sensitivity of CA 19-9 was 78.2% and in 37 studies involving 1,882 cases with
      benign pancreatic disease the specificity of CA 19-9 was 82.8%.
    explanation: >-
      Poruk et al. meta-analysis established CA 19-9 sensitivity of 78.2% and
      specificity of 82.8% for pancreatic carcinoma diagnosis.
  notes: >-
    Carbohydrate antigen 19-9 (CA 19-9) is the most widely used serum biomarker for
    PDAC. Elevated in approximately 80% of patients with PDAC. Used for monitoring
    treatment response and detecting recurrence, though not sufficiently sensitive
    or specific for screening.
- name: Carcinoembryonic Antigen (CEA)
  evidence:
  - reference: PMID:23331006
    reference_title: "The clinical utility of CA 19-9 in pancreatic adenocarcinoma: diagnostic and prognostic updates."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      From the combined analysis of studies reporting CEA, the sensitivity was
      44.2% (1,324 cases) and the specificity was 84.8% (656 cases).
    explanation: >-
      Poruk et al. meta-analysis showed CEA has lower sensitivity (44.2%) than
      CA 19-9 but comparable specificity (84.8%) for pancreatic carcinoma.
  notes: >-
    CEA may be elevated in PDAC and is sometimes used as an adjunct to CA 19-9 for
    monitoring, though it is less specific.
genetic:
- name: KRAS
  gene_term:
    preferred_term: KRAS
    term:
      id: hgnc:6407
      label: KRAS
  association: Somatic Gain-of-Function Mutation
  inheritance:
  - name: Somatic
  evidence:
  - reference: PMID:33347393
    reference_title: 'Clinical Effect of Driver Mutations of KRAS, CDKN2A/P16, TP53, and SMAD4 in Pancreatic Cancer: A Meta-Analysis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This systematic review and meta-analysis supports the use of driver mutations in the P53, SMAD4, and KRAS genes as prognostic markers for pancreatic cancer.
    explanation: Directly supports KRAS as an established driver mutation and prognostic marker in pancreatic cancer.
  - reference: DOI:10.3389/fmed.2024.1369136
    reference_title: "Targeting KRAS mutations in pancreatic cancer: opportunities for future strategies"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the case of pancreatic ductal adenocarcinomas (PDAC), 90-92% harbor mutations
      in the oncogene KRAS, triggering canonical MAPK signaling. The smooth structure
      of the altered KRAS protein without a binding pocket and its affinity for GTP have,
      in the past, hampered drug development.
    explanation: >-
      Confirms KRAS mutations in 90-92% of PDAC and describes the structural challenges
      that have historically hampered therapeutic targeting of KRAS.
  notes: >-
    KRAS (12p12.1) activating mutations are present in approximately 90% of PDAC.
    The most common mutations are G12D (~40%), G12V (~30%), and G12R (~15%).
    KRAS mutations are considered the initiating oncogenic event and occur in
    pancreatic intraepithelial neoplasia (PanIN) precursor lesions.
- name: TP53
  gene_term:
    preferred_term: TP53
    term:
      id: hgnc:11998
      label: TP53
  association: Somatic Loss-of-Function Mutation
  inheritance:
  - name: Somatic
  evidence:
  - reference: PMID:37404765
    reference_title: "Genomic landscape of clinically advanced KRAS wild-type pancreatic ductal adenocarcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the KRAS mutated group had a significantly higher percentage of TP53
      (mutated vs wild-type: 80.2% vs 47.6%, p <0.0001)
    explanation: >-
      Foundation Medicine genomic profiling of 9,444 advanced PDAC cases showed TP53
      mutations in 80.2% of KRAS-mutated PDAC.
  notes: >-
    TP53 (17p13.1) is mutated in approximately 75% of PDAC. Loss of TP53
    function disables cell cycle checkpoints and apoptotic responses to DNA
    damage, cooperating with KRAS to drive malignant transformation.
- name: SMAD4
  gene_term:
    preferred_term: SMAD4
    term:
      id: hgnc:6770
      label: SMAD4
  association: Somatic Loss-of-Function Mutation
  inheritance:
  - name: Somatic
  evidence:
  - reference: PMID:37404765
    reference_title: "Genomic landscape of clinically advanced KRAS wild-type pancreatic ductal adenocarcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SMAD4 (mutated vs wild-type: 26.8% vs 15.7%, p <0.0001)
    explanation: >-
      Foundation Medicine profiling showed SMAD4 mutations in 26.8% of KRAS-mutated
      PDAC. Higher rates reported in other studies reflect inclusion of homozygous
      deletions not captured by all assays.
  notes: >-
    SMAD4 (18q21.2) is inactivated in approximately 55% of PDAC through
    homozygous deletion or intragenic mutation. Loss of SMAD4 disrupts
    TGF-beta tumor-suppressive signaling and is associated with widespread
    metastatic disease.
- name: CDKN2A
  gene_term:
    preferred_term: CDKN2A
    term:
      id: hgnc:1787
      label: CDKN2A
  association: Somatic Loss-of-Function Mutation
  inheritance:
  - name: Somatic
  evidence:
  - reference: PMID:18772397
    reference_title: Core signaling pathways in human pancreatic cancers revealed by global genomic analyses.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This list includes the classic tumor suppressor genes CDKN2A (p16), SMAD4, and TP53, as well as genes that had not previously been implicated in pancreatic cancer development.
    explanation: Directly identifies CDKN2A/p16 as a classic tumor suppressor gene affected by homozygous deletion in pancreatic cancers.
  - reference: PMID:37404765
    reference_title: "Genomic landscape of clinically advanced KRAS wild-type pancreatic ductal adenocarcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CDKN2A (mutated vs wild-type: 56.2% vs 34.4%, p <0.0001)
    explanation: >-
      Foundation Medicine profiling showed CDKN2A alterations in 56.2% of KRAS-mutated
      PDAC. Higher rates in other studies include epigenetic silencing.
  notes: >-
    CDKN2A (9p21.3) encoding p16INK4a is inactivated in up to 90% of PDAC
    through homozygous deletion, mutation, or promoter methylation. Loss of
    p16 removes CDK4/6-mediated cell cycle inhibition.
- name: BRCA2
  gene_term:
    preferred_term: BRCA2
    term:
      id: hgnc:1101
      label: BRCA2
  association: Germline and Somatic Mutation
  inheritance:
  - name: Somatic
  evidence:
  - reference: PMID:31157963
    reference_title: "Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with a germline BRCA1 or BRCA2 mutation make up a small subgroup of
      those with metastatic pancreatic cancer. The poly(adenosine diphosphate-ribose)
      polymerase (PARP) inhibitor olaparib has had antitumor activity in this population.
    explanation: >-
      The POLO trial confirmed that BRCA-mutated PDAC patients represent a distinct
      subgroup that responds to PARP inhibition, validating the clinical relevance
      of BRCA2 mutations in PDAC.
  notes: >-
    BRCA2 germline mutations confer increased risk of PDAC and are found in
    approximately 5-7% of familial cases. BRCA2-deficient tumors have
    homologous recombination deficiency and may respond to platinum-based
    chemotherapy and PARP inhibitors.
environmental:
- name: Tobacco Smoking
  exposure_term:
    preferred_term: exposure to tobacco smoking
    term:
      id: ECTO:6000029
      label: exposure to tobacco smoking
  influences_mechanisms:
  - target: KRAS Oncogene Activation
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Pointed at the node this entry calls the initiating oncogenic event,
      because that is where a carcinogen exposure enters the graph. The route
      is left unknown deliberately: this entry's own description proposes that
      tobacco carcinogens promote KRAS mutations, but no cited sentence says
      so. The second item is carried precisely because it limits the first,
      and the limit is easy to miss: the headline relative risk is for
      pancreatic diseases as a class, and the same abstract reports that
      tobacco's effect on pancreatitis is larger than its effect on pancreatic
      cancer.
    evidence:
    - reference: PMID:24509242
      reference_title: "Factors that affect risk for pancreatic disease in the general population: a systematic review and meta-analysis of prospective cohort studies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Current tobacco use was the single most important risk factor for pancreatic diseases (RR, 1.87; 95% CI, 1.54-2.27), followed by obesity (RR, 1.48; 95% CI, 1.15-1.92) and heavy use of alcohol (RR, 1.37; 95% CI, 1.19-1.58)"
      explanation: >-
        Meta-analysis of 51 prospective cohorts giving tobacco the largest
        relative risk of the factors examined. Quoted whole so the comparison
        with obesity and alcohol travels with it. The outcome is pancreatic
        diseases, not this node.
    - reference: PMID:24509242
      reference_title: "Factors that affect risk for pancreatic disease in the general population: a systematic review and meta-analysis of prospective cohort studies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Tobacco and heavy use of alcohol had bigger effects on risk of acute pancreatitis and chronic pancreatitis than pancreatic cancer"
      explanation: >-
        The same abstract's own qualifier: the tobacco effect is larger for
        acute and chronic pancreatitis than for pancreatic cancer. Carried
        here so the headline figure is not read as a cancer-specific estimate.
  - target: Chronic Pancreatic Inflammation
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The second link, added once the entry had an inflammation node to receive it.
      This is where the cited meta-analysis's evidence is actually strongest: the
      qualifier that limits the KRAS link above - that tobacco's effect on
      pancreatitis exceeds its effect on pancreatic cancer - is direct support here.
      The route from smoke constituents to pancreatic inflammation is not traced by
      the abstract, so the intermediates stay unknown.
    evidence:
    - reference: PMID:24509242
      reference_title: "Factors that affect risk for pancreatic disease in the general population: a systematic review and meta-analysis of prospective cohort studies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Tobacco and heavy use of alcohol had bigger effects on risk of acute pancreatitis and chronic pancreatitis than pancreatic cancer"
      explanation: >-
        Names chronic pancreatitis as an outcome on which tobacco acts more strongly
        than on the cancer, which is the node this link targets.
  description: >-
    Cigarette smoking is the most well-established modifiable risk factor for PDAC,
    approximately doubling the risk. Tobacco carcinogens are metabolized in the
    pancreas and may promote KRAS mutations.
  evidence:
  - reference: PMID:34002083
    reference_title: 'Pancreatic cancer epidemiology: understanding the role of lifestyle and inherited risk factors.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: there are key modifiable risk factors for pancreatic cancer such as cigarette smoking, obesity, diabetes and alcohol intake.
    explanation: Directly identifies cigarette smoking as a leading modifiable risk factor for pancreatic cancer.
  - reference: PMID:24509242
    reference_title: "Factors that affect risk for pancreatic disease in the general population: a systematic review and meta-analysis of prospective cohort studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Current tobacco use was the single most important risk factor for pancreatic
      diseases (RR, 1.87; 95% CI, 1.54-2.27)
    explanation: >-
      Meta-analysis of 51 population-based prospective cohort studies
      identified tobacco use as the single most important modifiable risk
      factor for pancreatic diseases with an RR of 1.87. The outcome measured
      is pancreatic diseases as a class, and the same abstract reports that
      tobacco has a bigger effect on acute and chronic pancreatitis than on
      pancreatic cancer, so this figure is not a cancer-specific estimate.
- name: Chronic Pancreatitis
  influences_mechanisms:
  - target: Chronic Pancreatic Inflammation
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Retargeted from KRAS Oncogene Activation once this entry modeled the
      inflammation it acts on. Nothing intervenes: sustained pancreatic inflammation
      is what chronic pancreatitis is, so this is the one link in the block where the
      exposure and the node it reaches are the same process rather than separated by
      an untraced route.
    evidence:
    - reference: PMID:35142721
      reference_title: "Chronic Pancreatitis Is a Risk Factor for Pancreatic Cancer, and Incidence Increases With Duration of Disease: A Systematic Review and Meta-analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "There is an increased risk of PDAC in patients with CP, and incidence rates increase with CP disease duration."
      explanation: >-
        Cancer specific and dose-responsive, which is why it is the strongest of the
        three exposures here. PARTIAL because it measures cancer incidence rather
        than the inflammation this link targets.
    - reference: PMID:17349585
      reference_title: Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "However, if these mice are challenged with a mild form of chronic pancreatitis, they develop the full spectrum of PanINs and invasive PDA."
      explanation: >-
        The experimental counterpart: inducing chronic pancreatitis is what supplies
        the inflammatory state this link targets, and doing so is sufficient to
        release the neoplastic sequence in KRAS-mutant animals.
  description: >-
    Long-standing chronic pancreatitis increases PDAC risk approximately 10-15 fold.
    Chronic inflammation promotes ductal cell proliferation and accumulation of
    oncogenic mutations.
  notes: >-
    Chronic pancreatitis is a disease state rather than an exposure, so this entry
    sits in the class of `environmental:` items discussed in issue #8185. The
    comorbidity now exists --
    `kb/comorbidities/com_Chronic_Pancreatitis__Pancreatic_Ductal_Adenocarcinoma.yaml`,
    added in dismech#8296 -- and this row is deliberately kept rather than folded
    into it, which resolves the open question this note previously recorded.

    The two divide the labour. This row carries the mechanistic route into the
    pathograph: the `influences_mechanisms` link onto Chronic Pancreatic
    Inflammation, with the KRAS-mutant mouse experiment that shows inducing
    pancreatitis is sufficient to release the neoplastic sequence. A comorbidity
    entry has no pathograph link to offer, so folding this row in would lose that.
    The comorbidity carries the disease-disease epidemiology as a directed,
    queryable A_BEFORE_B risk edge with a magnitude. Both cite PMID:35142721;
    the comorbidity additionally carries the 1993 cohort standardized incidence
    ratio, which this row does not need.
  evidence:
  - reference: PMID:35142721
    reference_title: "Chronic Pancreatitis Is a Risk Factor for Pancreatic Cancer, and Incidence Increases With Duration of Disease: A Systematic Review and Meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There is an increased risk of PDAC in patients with CP, and incidence rates
      increase with CP disease duration.
    explanation: >-
      Gandhi et al. meta-analysis demonstrated a 22.6-fold increased risk of PDAC
      in chronic pancreatitis patients, with risk persisting after excluding
      surveillance bias.
- name: Obesity and Diet
  influences_mechanisms:
  - target: Chronic Pancreatic Inflammation
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Retargeted from KRAS Oncogene Activation. The limitation that made this link
      weak against the oncogene - that the meta-analysis measures pancreatic diseases
      as a class rather than the cancer - is much less of a stretch against an
      inflammation node, since pancreatitis is one of the diseases in that class. The
      route from adiposity to pancreatic inflammation is still not traced by the
      abstract, so the intermediates stay unknown, and the diet half of this exposure
      is not separately evidenced here at all.
    evidence:
    - reference: PMID:24509242
      reference_title: "Factors that affect risk for pancreatic disease in the general population: a systematic review and meta-analysis of prospective cohort studies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Current tobacco use was the single most important risk factor for pancreatic diseases (RR, 1.87; 95% CI, 1.54-2.27), followed by obesity (RR, 1.48; 95% CI, 1.15-1.92) and heavy use of alcohol (RR, 1.37; 95% CI, 1.19-1.58)"
      explanation: >-
        Gives obesity the second largest relative risk in the same ranking.
        Quoted whole rather than as the obesity clause alone, so that the
        exposure's rank among the others is visible.
  description: >-
    Obesity and high body mass index are associated with increased PDAC risk.
    High-fat diets and processed meat consumption have also been linked to
    elevated risk.
  evidence:
  - reference: PMID:24509242
    reference_title: "Factors that affect risk for pancreatic disease in the general population: a systematic review and meta-analysis of prospective cohort studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      followed by obesity (RR, 1.48; 95% CI, 1.15-1.92)
    explanation: >-
      Meta-analysis of prospective cohort studies identified obesity as the
      second most important risk factor for pancreatic diseases with an RR of 1.48.
treatments:
- name: Surgical Resection (Whipple Procedure)
  description: >-
    Pancreaticoduodenectomy (Whipple procedure) is the only potentially curative
    treatment for PDAC but is feasible in only 15-20% of patients at diagnosis.
    R0 resection followed by adjuvant chemotherapy provides the best long-term
    survival outcomes.
  evidence:
  - reference: PMID:28129987
    reference_title: "Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Eligible patients were aged 18 years or older and had undergone complete
      macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1
      resection).
    explanation: >-
      The ESPAC-4 trial enrolled patients who underwent complete macroscopic resection
      for PDAC, confirming surgical resection as a standard treatment approach with
      adjuvant chemotherapy improving outcomes.
  treatment_term:
    preferred_term: pancreaticoduodenectomy (Whipple procedure)
    term:
      id: NCIT:C15356
      label: Whipple Procedure
- name: FOLFIRINOX Chemotherapy
  description: >-
    Combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin. Used as
    first-line treatment for metastatic PDAC in fit patients and as adjuvant therapy
    after surgical resection. Provides superior survival compared to gemcitabine
    alone but with greater toxicity.
  evidence:
  - reference: PMID:30575490
    reference_title: "FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Adjuvant therapy with a modified FOLFIRINOX regimen led to significantly longer
      survival than gemcitabine among patients with resected pancreatic cancer, at the
      expense of a higher incidence of toxic effects.
    explanation: >-
      The PRODIGE 24 trial demonstrated that adjuvant modified FOLFIRINOX significantly
      improved disease-free and overall survival compared to gemcitabine in resected
      PDAC patients.
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: NCIT:C15632
      label: Chemotherapy
  regimen_term:
    preferred_term: modified FOLFIRINOX regimen
    term:
      id: NCIT:C11764
      label: Folfirinox Regimen
- name: Gemcitabine-Based Chemotherapy
  description: >-
    Gemcitabine monotherapy or in combination with nab-paclitaxel is a standard
    treatment for advanced PDAC. Gemcitabine plus nab-paclitaxel provides improved
    survival over gemcitabine alone and is better tolerated than FOLFIRINOX.
  evidence:
  - reference: PMID:24131140
    reference_title: "Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      nab-paclitaxel plus gemcitabine significantly improved overall survival,
      progression-free survival, and response rate, but rates of peripheral neuropathy
      and myelosuppression were increased.
    explanation: >-
      The Von Hoff et al. phase 3 trial demonstrated that nab-paclitaxel plus
      gemcitabine significantly improved overall survival (8.5 vs 6.7 months) in
      metastatic pancreatic adenocarcinoma.
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: NCIT:C15632
      label: Chemotherapy
- name: PARP Inhibitor Therapy
  description: >-
    Olaparib is approved as maintenance therapy for BRCA-mutated metastatic PDAC
    that has not progressed on first-line platinum-based chemotherapy, based on
    the POLO trial.
  evidence:
  - reference: DOI:10.1200/jco.21.01604
    reference_title: "Overall Survival Results From the POLO Trial: A Phase III Study of Active Maintenance Olaparib Versus Placebo for Germline BRCA-Mutated Metastatic Pancreatic Cancer"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The phase III POLO study demonstrated significant progression-free survival (PFS) benefit for active olaparib maintenance therapy versus placebo for patients with metastatic pancreatic adenocarcinoma and a germline BRCA mutation.
    explanation: The phase III POLO trial supports maintenance olaparib in germline BRCA-mutated metastatic pancreatic adenocarcinoma; folded in from the former Metastatic_Pancreatic_Adenocarcinoma entry.
  - reference: PMID:31157963
    reference_title: "Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to
      evaluate the efficacy of olaparib as maintenance therapy in patients who had a
      germline BRCA1 or BRCA2 mutation and metastatic pancreatic cancer and disease
      that had not progressed during first-line platinum-based chemotherapy.
    explanation: >-
      The POLO trial demonstrated that maintenance olaparib significantly prolonged
      progression-free survival in germline BRCA-mutated metastatic pancreatic cancer
      patients who had not progressed on platinum-based chemotherapy.
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
- name: Daraxonrasib (RAS(ON) Multiselective Inhibitor)
  description: >-
    Daraxonrasib (RMC-6236) is an oral RAS(ON) multiselective, tri-complex
    inhibitor that binds cyclophilin A intracellularly to engage the active
    GTP-bound state of mutant and wild-type RAS (KRAS, NRAS, and HRAS, including
    G12, G13, and Q61 variants) and suppress downstream MAPK signaling. In the
    phase 3 RASolute 302 trial in previously treated metastatic PDAC, daraxonrasib
    doubled median overall survival to 13.2 months versus 6.6 months with
    chemotherapy in the RAS G12 population (hazard ratio 0.40), directly drugging
    the near-universal KRAS oncogenic driver of PDAC that had long been considered
    undruggable.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: daraxonrasib
      term:
        id: CHEBI:746946
        label: daraxonrasib
  target_mechanisms:
  - target: KRAS Oncogene Activation
    treatment_effect: INHIBITS
    description: >-
      Daraxonrasib directly inhibits the active RAS(ON) state produced by
      oncogenic KRAS codon-12 mutations, the initiating driver of PDAC,
      suppressing constitutive RAS-MAPK signaling.
    evidence:
    - reference: PMID:42223072
      reference_title: "Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Daraxonrasib is an oral RAS(ON) multiselective, tri-complex inhibitor of
        the active guanosine triphosphate-bound state of mutant and wild-type RAS.
      explanation: >-
        The RASolute 302 report describes daraxonrasib's mechanism as direct
        inhibition of the active GTP-bound RAS state driven by mutant KRAS in PDAC.
  evidence:
  - reference: clinicaltrials:NCT06625320
    reference_title: 'RASolute 302: A Phase 3 Multicenter, Open-label, Randomized Study of Daraxonrasib (RMC-6236) Versus Investigator''s Choice of Standard of Care Therapy in Patients With Previously Treated Metastatic Pancreatic Ductal Adenocarcinoma (PDAC)'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The purpose of this study is to evaluate the safety and efficacy of a novel RAS(ON) inhibitor compared to standard(s) of care (SOC) treatment.
    explanation: ClinicalTrials.gov documents RASolute 302 as a phase 3 evaluation of the RAS(ON) inhibitor daraxonrasib versus standard-of-care chemotherapy in previously treated metastatic PDAC.
  - reference: PMID:42223072
    reference_title: Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Daraxonrasib is an oral RAS(ON) multiselective, tri-complex inhibitor of the active guanosine triphosphate-bound state of mutant and wild-type RAS.
    explanation: Establishes daraxonrasib's mechanism of action as a RAS(ON) multiselective tri-complex inhibitor of the active GTP-bound state of mutant and wild-type RAS, the basis for its target_mechanisms link to KRAS-centered signaling.
  - reference: PMID:42223072
    reference_title: Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The median overall survival in the RAS G12 population was 13.2 months with daraxonrasib and 6.6 months with chemotherapy, and the median overall survival in the overall population was 13.2 months and 6.7 months, respectively; the hazard ratio was 0.40 in both populations (P<0.001).
    explanation: RASolute 302 demonstrated a significant overall survival benefit for daraxonrasib over chemotherapy (hazard ratio for death 0.40) in previously treated metastatic PDAC.
  - reference: PMID:42223072
    reference_title: "Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The median overall survival in the RAS G12 population was 13.2 months with
      daraxonrasib and 6.6 months with chemotherapy
    explanation: >-
      The phase 3 RASolute 302 trial demonstrated that daraxonrasib significantly
      prolonged overall survival versus chemotherapy in previously treated
      metastatic PDAC with RAS G12 mutations (hazard ratio 0.40).
- name: Mutant KRAS Vaccine (Immunologic Interception)
  description: >-
    Because activating KRAS mutations (G12D, G12V, G12R) are the near-universal
    initiating event in PDAC and are shared across patients, the mutant KRAS
    protein is an attractive shared tumor neoantigen for vaccination — the basis of
    an "interception" strategy aiming to raise anti-mutant-KRAS T-cell immunity in
    high-risk individuals and in the minimal-residual-disease setting before
    macroscopic recurrence. In the phase 1 AMPLIFY-201 trial, the
    lymph-node-targeted amphiphile vaccine ELI-002 2P (G12D/G12R mKRAS peptides plus CpG
    adjuvant) induced mutant-KRAS-specific CD4+/CD8+ T-cell responses in most
    patients with KRAS-mutated pancreatic or colorectal cancer. Application as true
    primary prevention in high-risk individuals is under investigation.
  therapeutic_modality: VACCINE
  treatment_term:
    preferred_term: vaccination
    term:
      id: NCIT:C15346
      label: Vaccination
  target_mechanisms:
  - target: KRAS Oncogene Activation
    treatment_effect: INHIBITS
    description: >-
      The vaccine presents mutant-KRAS neoantigens to prime cytotoxic and helper
      T cells that recognize and eliminate cells expressing the oncogenic KRAS
      variant — an immunologic route to suppressing the KRAS-driven clone, distinct
      from direct pharmacologic RAS inhibition.
    evidence:
    - reference: PMID:38195752
      reference_title: "Lymph-node-targeted, mKRAS-specific amphiphile vaccine in pancreatic and colorectal cancer: the phase 1 AMPLIFY-201 trial."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "ELI-002 2P was safe and induced considerable T cell responses in patients with immunotherapy-recalcitrant KRAS-mutated tumors."
      explanation: >-
        Demonstrates that a mutant-KRAS vaccine induces mKRAS-specific T-cell
        responses in KRAS-mutated tumors, supporting immune targeting of the
        KRAS-oncogene-activated clone.
  evidence:
  - reference: PMID:38195752
    reference_title: "Lymph-node-targeted, mKRAS-specific amphiphile vaccine in pancreatic and colorectal cancer: the phase 1 AMPLIFY-201 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cancer vaccine ELI-002 2P enhances lymph node delivery and immune response using amphiphile (Amph) modification of G12D and G12R mutant KRAS (mKRAS) peptides (Amph-Peptides-2P) together with CpG oligonucleotide adjuvant (Amph-CpG-7909)."
    explanation: >-
      Describes the mutant-KRAS amphiphile vaccine platform evaluated in the phase 1
      AMPLIFY-201 trial.
clinical_trials:
- name: NCT06625320
  description: >-
    RASolute 302: a phase 3, international, open-label, randomized trial comparing
    daraxonrasib (RMC-6236) with the investigator's choice of standard chemotherapy
    in patients with previously treated metastatic PDAC. The trial met its dual
    primary endpoints of overall survival and progression-free survival in the
    RAS G12 population.
  phase: PHASE_III
  status: ACTIVE_NOT_RECRUITING
  target_phenotypes:
  - preferred_term: Neoplasm of the pancreas
    term:
      id: HP:0002894
      label: Neoplasm of the pancreas
  evidence:
  - reference: clinicaltrials:NCT06625320
    reference_title: "RASolute 302: A Phase 3 Multicenter, Open-label, Randomized Study of Daraxonrasib (RMC-6236) Versus Investigator's Choice of Standard of Care Therapy in Patients With Previously Treated Metastatic Pancreatic Ductal Adenocarcinoma (PDAC)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The purpose of this study is to evaluate the safety and efficacy of a novel
      RAS(ON) inhibitor compared to standard(s) of care (SOC) treatment.
    explanation: >-
      ClinicalTrials.gov confirms RASolute 302 (NCT06625320) evaluated the RAS(ON)
      inhibitor daraxonrasib against standard-of-care chemotherapy in mPDAC.
  - reference: PMID:42223072
    reference_title: "Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among patients with previously treated mPDAC, treatment with daraxonrasib led
      to significantly longer overall survival and progression-free survival than
      chemotherapy.
    explanation: >-
      The primary-results publication reports that RASolute 302 met its overall
      survival and progression-free survival endpoints favoring daraxonrasib.
discussions:
- discussion_id: gap_pdac_caf_program_t_cell_exclusion
  prompt: >-
    Which cancer-associated fibroblast programs actively cause T-cell exclusion
    and checkpoint resistance in PDAC, and which stromal programs are
    tumor-restraining or merely correlative with desmoplastic burden?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Desmoplastic Stroma
  - pathophysiology#CAF-Mediated T Cell Exclusion
  - pathophysiology#Immune Evasion
  rationale: >-
    PDAC desmoplasia is not a single therapeutic target: some CAF states may
    exclude effector T cells, whereas others may restrain invasion. A
    patient-derived organ-on-chip experiment can test whether specific CAF
    programs are causal for immune exclusion and whether reprogramming them
    improves T-cell cytotoxicity without removing tumor-restraining stroma.
  proposed_experiments:
  - experiment_id: exp_pdac_patient_ooc_caf_t_cell_exclusion
    name: Patient-derived PDAC organ-on-chip CAF reprogramming and T-cell infiltration assay
    description: >-
      Assemble a patient-derived PDAC organoid organ-on-chip with fibroblasts,
      endothelium, and immune cells; induce or suppress CAF programs including
      interferon-response CAF states; then measure T-cell infiltration,
      cytotoxicity, tumor viability, and stromal remodeling under checkpoint
      blockade.
    experiment_type:
      preferred_term: patient-derived organ-on-chip immunotherapy perturbation experiment
    model_systems:
    - name: Patient-derived PDAC tumor-microenvironment organ-on-chip
      description: >-
        Microfluidic human PDAC model combining patient-derived tumor organoids
        with fibroblasts, endothelial cells, and immune cells so stromal
        crosstalk, T-cell migration, and drug response can be measured in a
        standardized ex vivo platform.
      experimental_model_type: ORGAN_ON_CHIP
      namo_type: namo:OrganOnChip
      organism:
        preferred_term: human
        term:
          id: NCBITaxon:9606
          label: Homo sapiens
      tissue_term:
        preferred_term: pancreas
        term:
          id: UBERON:0001264
          label: pancreas
      cell_types:
      - preferred_term: pancreatic ductal cell
        term:
          id: CL:0002079
          label: pancreatic ductal cell
      - preferred_term: fibroblast
        term:
          id: CL:0000057
          label: fibroblast
      - preferred_term: endothelial cell
        term:
          id: CL:0000115
          label: endothelial cell
      - preferred_term: T cell
        term:
          id: CL:0000084
          label: T cell
      cell_source: patient-derived organoids plus matched stromal and immune-cell compartments
      culture_system: perfused microfluidic organ-on-chip with extracellular-matrix scaffold
    perturbations:
    - name: CAF subtype induction and depletion
      target: pathophysiology#Desmoplastic Stroma
      description: >-
        Induce, suppress, or selectively deplete CAF states to separate
        immune-excluding and tumor-restraining stromal programs.
      genes:
      - preferred_term: FAP
      biological_processes:
      - preferred_term: extracellular matrix organization
        term:
          id: GO:0030198
          label: extracellular matrix organization
    - name: STING-driven interferon-response CAF induction
      target: pathophysiology#CAF-Mediated T Cell Exclusion
      description: >-
        STING agonism or matched interferon-response induction used to test
        whether an interferon-response CAF state decreases invasion and improves
        antitumor immune activity.
      biological_processes:
      - preferred_term: type I interferon signaling pathway
        term:
          id: GO:0060337
          label: type I interferon-mediated signaling pathway
    - name: Immune checkpoint blockade
      target: pathophysiology#Immune Evasion
      description: >-
        Anti-PD-1/PD-L1 or matched checkpoint blockade applied with CAF
        perturbation to test whether stromal reprogramming is required for
        T-cell cytotoxicity.
      treatment_term:
        preferred_term: immunotherapy
        term:
          id: NCIT:C15262
          label: Immunotherapy
    readouts:
    - name: T-cell infiltration and cytotoxicity
      target: pathophysiology#CAF-Mediated T Cell Exclusion
      description: >-
        Spatial T-cell entry into tumor organoid regions, activation markers,
        and tumor-cell killing after CAF-state perturbation.
      biological_processes:
      - preferred_term: T cell activation
        term:
          id: GO:0042110
          label: T cell activation
      assays:
      - preferred_term: high-content live imaging
      - preferred_term: cytotoxicity assay
      direction: NEGATIVE
    - name: CAF-state trajectory
      target: pathophysiology#Desmoplastic Stroma
      description: >-
        Single-cell and spatial profiling of inflammatory, myofibroblastic, and
        interferon-response CAF programs after stromal perturbation.
      assays:
      - preferred_term: single-cell transcriptomic profiling
      - preferred_term: spatial transcriptomic profiling
      direction: POSITIVE
    - name: Tumor organoid viability under checkpoint blockade
      target: pathophysiology#Immune Evasion
      description: Tumor-cell survival after combined CAF perturbation and checkpoint blockade.
      assays:
      - preferred_term: cell viability assay
      direction: NEGATIVE
    controls:
    - name: Tumor organoid without CAF compartment
      description: Patient-derived PDAC organoid chip lacking fibroblasts.
    - name: CAF-intact chip without T cells
      description: Stromal chip lacking effector T cells to distinguish direct stromal effects from immune-mediated killing.
    - name: Isotype-control checkpoint antibody
      description: Matched antibody control for checkpoint blockade.
    decision_criterion: >-
      A causal CAF immune-exclusion program is supported if its induction
      reduces T-cell entry or killing and its suppression restores checkpoint
      response. A tumor-restraining CAF state is supported if induction lowers
      invasion or viability while preserving or improving T-cell function.
    would_support:
    - pathophysiology#CAF-Mediated T Cell Exclusion
    - pathophysiology#Immune Evasion
    would_refute:
    - pathophysiology#CAF-Mediated T Cell Exclusion
    evidence:
    - reference: PMID:41610338
      reference_title: "A Patient-Derived Organ-on-Chip Platform for Modeling the Tumor Microenvironment and Drug Responses in Pancreatic Cancer."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "incorporating PDOs with key components of the TME (fibroblasts, endothelial cells, and immune cells) within a microfluidic system"
      explanation: >-
        Provides the recent patient-derived organ-on-chip precedent for a
        PDAC tumor-microenvironment experiment with stromal and immune
        compartments.
    - reference: PMID:41610338
      reference_title: "A Patient-Derived Organ-on-Chip Platform for Modeling the Tumor Microenvironment and Drug Responses in Pancreatic Cancer."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "model and assess the efficacy of immune checkpoint blockade for T cell cytotoxicity in PDAC"
      explanation: >-
        Supports using this platform to adjudicate checkpoint response in the
        presence of patient-derived stromal context.
    - reference: PMID:40215177
      reference_title: "Dissecting FAP+ Cell Diversity in Pancreatic Cancer Uncovers an Interferon-Response Subtype of Cancer-Associated Fibroblasts with Tumor-Restraining Properties."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "identifies an ifCAF subtype that can be induced to suppress protumorigenic features of PDAC"
      explanation: >-
        Motivates testing CAF reprogramming rather than treating all desmoplasia
        as uniformly protumorigenic.
disease_term:
  preferred_term: pancreatic ductal adenocarcinoma
  term:
    id: MONDO:0005184
    label: pancreatic ductal adenocarcinoma
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0005184
      label: pancreatic ductal adenocarcinoma
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: MONDO provides an exact disease term for pancreatic ductal adenocarcinoma.
  icd10cm_mappings:
  - term:
      id: ICD10CM:C25.3
      label: Malignant neoplasm of pancreatic duct
    mapping_predicate: skos:exactMatch
    mapping_source: ICD-10-CM
    mapping_justification: ICD-10-CM provides an exact malignant neoplasm code for pancreatic duct.
  ncit_mappings:
  - term:
      id: NCIT:C9120
      label: Pancreatic Ductal Adenocarcinoma
    mapping_predicate: skos:exactMatch
    mapping_source: NCIT
    mapping_justification: NCIT provides an exact neoplasm term for pancreatic ductal adenocarcinoma.
datasets:
- accession: geo:GSE111672
  title: Integrating microarray-based spatial transcriptomics and single-cell RNA-seq reveals tissue architecture in pancreatic ductal adenocarcinomas
  description: >-
    Multimodal PDAC dataset combining spatial transcriptomics and single-cell RNA-seq
    from primary pancreatic tumors. Useful for resolving how malignant ductal cells,
    macrophages, dendritic cells, and fibroblast states are spatially organized within
    the tumor microenvironment.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MULTI_OMICS
  sample_types:
  - preferred_term: pancreatic tumor tissue
    tissue_term:
      preferred_term: pancreas
      term:
        id: UBERON:0001264
        label: pancreas
  sample_count: 23
  conditions:
  - primary pancreatic ductal adenocarcinoma
  publication: PMID:31932730
  notes: >-
    GEO reports six primary pancreatic cancer patients with matched single-cell and
    spatial transcriptomic profiling. Particularly relevant for spatial initialization
    and cell-neighborhood constraints in PhysiCell-style TME models.
- accession: geo:GSE154778
  title: Single-cell transcriptomics analysis of pancreatic primary tumor and metastatic biopsy tissues
  description: >-
    Single-cell RNA-seq of 10 pancreatic primary tumors and 6 metastatic biopsies.
    Captures tumor, stromal, and immune programs across primary and metastatic disease,
    making it useful for modeling dissemination and metastatic niche adaptation in PDAC.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_types:
  - preferred_term: pancreatic tumor tissue
    tissue_term:
      preferred_term: pancreas
      term:
        id: UBERON:0001264
        label: pancreas
  sample_count: 16
  conditions:
  - primary pancreatic ductal adenocarcinoma
  - metastatic pancreatic ductal adenocarcinoma
  publication: PMID:32988401
  notes: >-
    GEO reports 10 primary tumors and 6 metastatic lesion biopsies profiled on the
    10x Genomics Chromium platform. High-value bridge dataset between primary-tumor
    ecology and metastatic evolution.
- accession: geo:GSE155698
  title: Multimodal Mapping of the Tumor and Peripheral Blood Immune Landscape in Human Pancreatic Cancer
  description: >-
    Single-cell immune-focused PDAC resource spanning tumor tissue, adjacent normal
    pancreas, and peripheral blood mononuclear cells from pancreatic cancer patients,
    plus healthy-donor PBMC controls. Especially useful for linking the local TME to
    the systemic macroenvironment.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_types:
  - preferred_term: pancreatic tumor tissue
    tissue_term:
      preferred_term: pancreas
      term:
        id: UBERON:0001264
        label: pancreas
  - preferred_term: adjacent normal pancreatic tissue
    tissue_term:
      preferred_term: pancreas
      term:
        id: UBERON:0001264
        label: pancreas
  - preferred_term: peripheral blood
    tissue_term:
      preferred_term: blood
      term:
        id: UBERON:0000178
        label: blood
  sample_count: 41
  conditions:
  - pancreatic ductal adenocarcinoma tumor tissue
  - adjacent normal pancreas
  - pancreatic cancer patient PBMCs
  - healthy donor PBMCs
  publication: PMID:34296197
  notes: >-
    GEO reports 16 PDAC tissue samples, 3 adjacent normal pancreas samples, 16
    patient PBMC samples, and 4 healthy-donor PBMC samples. This is a strong anchor
    for modeling immune composition across tumor and circulation.
- accession: geo:GSE62452
  title: Microarray gene-expression profiles of 69 pancreatic tumors and 61 adjacent non-tumor tissue from patients with pancreatic ductal adenocarcinoma
  description: >-
    Large paired bulk expression cohort of PDAC tumors and adjacent non-tumor tissue.
    Useful as a broader transcriptomic reference set for tumor-versus-normal contrasts
    and for anchoring subtype-level or pathway-level signatures in a larger patient cohort.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_types:
  - preferred_term: pancreatic tumor tissue
    tissue_term:
      preferred_term: pancreas
      term:
        id: UBERON:0001264
        label: pancreas
  sample_count: 130
  conditions:
  - pancreatic ductal adenocarcinoma tumor tissue
  - adjacent non-tumor pancreatic tissue
  publication: PMID:27197190
  notes: >-
    GEO reports 69 pancreatic tumors and 61 adjacent non-tumor tissues, with earlier
    Affymetrix data from GSE28735 incorporated into the merged normalized cohort.
    Useful as a bulk-expression complement to the single-cell and spatial resources above.
computational_models:
- name: PDAC CAF-Mediated Invasion PhysiCell Model
  description: >-
    Grammar-based PhysiCell agent-based model of pancreatic ductal adenocarcinoma
    neoplastic cells and cancer-associated fibroblasts. The model encodes
    fibroblast-mediated invasion, epithelial-mesenchymal state switching, and
    ECM-dependent motility tradeoffs using human-interpretable cell rules
    informed by PDAC spatial transcriptomics and coculture data.
  model_type: AGENT_BASED
  repository_url: https://github.com/PhysiCell-Models/grammar_samples/tree/v2.0.1/user_projects/epi_caf_invasion
  model_id: grammar_samples:v2.0.1/user_projects/epi_caf_invasion
  base_model: PhysiCell grammar manuscript release DOI:10.5281/zenodo.16285252
  model_software: PhysiCell
  model_format: C++/XML/CSV
  publication: DOI:10.1016/j.cell.2025.06.048
  modeled_mechanisms:
  - target: Desmoplastic Stroma
    description: >-
      Implements ECM-driven fibroblast motility and epithelial-mesenchymal state
      switching encoded in `config/cell_rules.csv` for the stromal invasion program.
  findings:
  - statement: ECM increases epithelial-to-mesenchymal switching of tumor epithelial cells in the executable PDAC invasion model.
    supporting_text: epithelial_tumor,ecm,increases,transform to mesenchymal_tumor,0.01,0.01,4,0
  - statement: Fibroblast migration is explicitly controlled by ECM-dependent rules in the invasion model.
    supporting_text: fibroblast,ecm,increases,migration speed,3.470551875,9.999679617,1.153017946,0
  variables:
  - name: inflammatory_signal
    dataset_identifier: inflammatory_signal
    description: Generic inflammatory signaling field used to bias migration and mesenchymal-to-epithelial state transitions.
    unit: dimensionless field
  - name: ecm
    dataset_identifier: ecm
    description: Extracellular-matrix density field driving stromal invasion and epithelial-mesenchymal plasticity.
    unit: dimensionless field
    mappings_list:
    - preferred_term: Extracellular matrix
      term:
        id: GO:0031012
        label: extracellular matrix
  - name: epithelial_normal_cells
    dataset_identifier: epithelial_normal
    description: Abundance of non-malignant epithelial agents in the coculture invasion simulation.
    unit: cells
    mappings_list:
    - preferred_term: epithelial cell
      term:
        id: CL:0000066
        label: epithelial cell
  - name: mesenchymal_normal_cells
    dataset_identifier: mesenchymal_normal
    description: Abundance of non-malignant mesenchymal-state agents in the invasion simulation.
    unit: cells
    mappings_list:
    - preferred_term: mesenchymal cell
      term:
        id: CL:0008019
        label: mesenchymal cell
  - name: fibroblast_cells
    dataset_identifier: fibroblast
    description: Abundance of fibroblast / CAF-like agents in the invasion simulation.
    unit: cells
    mappings_list:
    - preferred_term: fibroblast
      term:
        id: CL:0000057
        label: fibroblast
  - name: epithelial_tumor_cells
    dataset_identifier: epithelial_tumor
    description: Abundance of epithelial-state malignant agents in the invasion simulation.
    unit: cells
    mappings_list:
    - preferred_term: epithelial tumor cell
      term:
        id: CL:0000066
        label: epithelial cell
  - name: mesenchymal_tumor_cells
    dataset_identifier: mesenchymal_tumor
    description: Abundance of mesenchymal-state malignant agents in the invasion simulation.
    unit: cells
    mappings_list:
    - preferred_term: mesenchymal tumor cell
      term:
        id: CL:0008019
        label: mesenchymal cell
  notes: >-
    Manuscript-synced sample model from the official PhysiCell grammar_samples
    release. Relevant configs include `config/PhysiCell_settings_PDAC.xml`,
    the rule table in `config/cell_rules.csv`, and coculture initial conditions
    under `config/ics/`.
- name: PDAC Immunotherapy PhysiCell Model
  description: >-
    Grammar-based PhysiCell agent-based PDAC tumor-immune model initialized
    from PDAC tissue compositions. The model simulates combination therapy with
    GVAX, nivolumab, and urelumab across heterogeneous baseline microenvironment
    states and is a strong executable analogue of PDAC immune-excluded ecology.
  model_type: AGENT_BASED
  repository_url: https://github.com/PhysiCell-Models/grammar_samples/tree/v2.0.1/user_projects/pdac_therapy
  model_id: grammar_samples:v2.0.1/user_projects/pdac_therapy
  base_model: PhysiCell grammar manuscript release DOI:10.5281/zenodo.16285252
  model_software: PhysiCell
  model_format: C++/XML/CSV
  publication: DOI:10.1016/j.cell.2025.06.048
  modeled_mechanisms:
  - target: Immune Evasion
    description: >-
      Encodes PD-L1-dependent suppression of T-cell motility and attack probabilities,
      plus macrophage inflammatory-state rules, in `config/cell_rules.csv`.
  findings:
  - statement: Contact with PD-L1-high tumor cells reduces CD8 T-cell migration in the executable PDAC immunotherapy model.
    supporting_text: PD-1lo_CD137lo_CD8_Tcell,contact with PD-L1hi_tumor,decreases,migration speed,0,0.1,2,0
  - statement: Anti-inflammatory signals decrease CD8 T-cell attack against tumor cells in the executable PDAC immunotherapy model.
    supporting_text: PD-1lo_CD137hi_CD8_Tcell,anti-inflammatory factor,decreases,attack PD-L1hi_tumor,0,2.5,2,0
  - statement: Macrophage oxygen sensing controls pro- versus anti-inflammatory factor secretion in the executable PDAC immunotherapy model.
    supporting_text: macrophage,oxygen,decreases,anti-inflammatory factor secretion,0,5,4,0
  variables:
  - name: oxygen
    dataset_identifier: oxygen
    description: Diffusible oxygen field used to control tumor proliferation, macrophage polarization logic, and necrotic stress.
    unit: substrate density
    mappings_list:
    - preferred_term: dioxygen
      term:
        id: CHEBI:15379
        label: dioxygen
  - name: debris
    dataset_identifier: debris
    description: Extracellular dead-cell debris field that attracts macrophages and reflects local cell death burden.
    unit: substrate density
  - name: pro_inflammatory_factor
    dataset_identifier: pro-inflammatory factor
    description: Generic pro-inflammatory signaling field that boosts T-cell attack and chemotaxis in the model.
    unit: substrate density
  - name: anti_inflammatory_factor
    dataset_identifier: anti-inflammatory factor
    description: Generic anti-inflammatory signaling field that suppresses T-cell migration and attack in the model.
    unit: substrate density
  - name: PD-L1lo_tumor_cells
    dataset_identifier: PD-L1lo_tumor
    description: Abundance of PD-L1-low malignant epithelial agents in the PDAC immunotherapy simulation.
    unit: cells
    mappings_list:
    - preferred_term: epithelial tumor cell
      term:
        id: CL:0000066
        label: epithelial cell
  - name: PD-L1hi_tumor_cells
    dataset_identifier: PD-L1hi_tumor
    description: Abundance of PD-L1-high malignant epithelial agents in the PDAC immunotherapy simulation.
    unit: cells
    mappings_list:
    - preferred_term: epithelial tumor cell
      term:
        id: CL:0000066
        label: epithelial cell
    - preferred_term: Programmed cell death 1 ligand 1
      term:
        id: NCIT:C96024
        label: Programmed Cell Death 1 Ligand 1
  - name: macrophages
    dataset_identifier: macrophage
    description: Abundance of macrophage agents in the PDAC immunotherapy simulation.
    unit: cells
    mappings_list:
    - preferred_term: macrophage
      term:
        id: CL:0000235
        label: macrophage
  - name: PD-1hi_CD137lo_CD8_T_cells
    dataset_identifier: PD-1hi_CD137lo_CD8_Tcell
    description: Abundance of PD-1-high CD137-low CD8 T-cell agents in the PDAC immunotherapy simulation.
    unit: cells
    mappings_list:
    - preferred_term: PD-1-high CD137-low CD8 T cell
      term:
        id: CL:0000625
        label: CD8-positive, alpha-beta T cell
  - name: PD-1lo_CD137lo_CD8_T_cells
    dataset_identifier: PD-1lo_CD137lo_CD8_Tcell
    description: Abundance of PD-1-low CD137-low CD8 T-cell agents in the PDAC immunotherapy simulation.
    unit: cells
    mappings_list:
    - preferred_term: PD-1-low CD137-low CD8 T cell
      term:
        id: CL:0000625
        label: CD8-positive, alpha-beta T cell
  - name: PD-1hi_CD137hi_CD8_T_cells
    dataset_identifier: PD-1hi_CD137hi_CD8_Tcell
    description: Abundance of PD-1-high CD137-high CD8 T-cell agents in the PDAC immunotherapy simulation.
    unit: cells
    mappings_list:
    - preferred_term: PD-1-high CD137-high CD8 T cell
      term:
        id: CL:0000625
        label: CD8-positive, alpha-beta T cell
  - name: PD-1lo_CD137hi_CD8_T_cells
    dataset_identifier: PD-1lo_CD137hi_CD8_Tcell
    description: Abundance of PD-1-low CD137-high CD8 T-cell agents in the PDAC immunotherapy simulation.
    unit: cells
    mappings_list:
    - preferred_term: PD-1-low CD137-high CD8 T cell
      term:
        id: CL:0000625
        label: CD8-positive, alpha-beta T cell
  - name: PD-1hi_CD4_T_cells
    dataset_identifier: PD-1hi_CD4_Tcell
    description: Abundance of PD-1-high CD4 T-cell agents in the PDAC immunotherapy simulation.
    unit: cells
    mappings_list:
    - preferred_term: PD-1-high CD4 T cell
      term:
        id: CL:0000624
        label: CD4-positive, alpha-beta T cell
  - name: PD-1lo_CD4_T_cells
    dataset_identifier: PD-1lo_CD4_Tcell
    description: Abundance of PD-1-low CD4 T-cell agents in the PDAC immunotherapy simulation.
    unit: cells
    mappings_list:
    - preferred_term: PD-1-low CD4 T cell
      term:
        id: CL:0000624
        label: CD4-positive, alpha-beta T cell
  notes: >-
    Manuscript-synced sample model from the official PhysiCell grammar_samples
    release. Therapy-specific initial-condition files are stored in
    `config/ic_cells/`, and the core executable interaction logic is in
    `config/cell_rules.csv`.
references:
- reference: DOI:10.1146/annurev-pathmechdis-031621-024600
  title: "Tumor Microenvironment in Pancreatic Cancer Pathogenesis and Therapeutic Resistance"
  found_in:
  - Pancreatic_Ductal_Adenocarcinoma-deep-research-falcon.md
  findings:
  - statement: PDAC has a prominent and spatially heterogeneous stromal microenvironment that meaningfully shapes treatment resistance.
    supporting_text: Pancreatic ductal adenocarcinoma (PDAC) features a prominent stromal microenvironment with remarkable cellular and spatial heterogeneity that meaningfully impacts disease biology and treatment resistance.
- reference: DOI:10.1158/2159-8290.CD-23-0428
  title: Senescence Defines a Distinct Subset of Myofibroblasts that Orchestrates Immunosuppression in Pancreatic Cancer
  found_in:
  - Pancreatic_Ductal_Adenocarcinoma-deep-research-falcon.md
  findings:
  - statement: Functionally distinct fibroblast states are part of the immunosuppressive circuitry of pancreatic cancer.
    supporting_text: Senescence defines a distinct subset of myofibroblasts that orchestrates immunosuppression in pancreatic cancer.
- reference: DOI:10.1001/jamaoncol.2024.1930
  title: Pancreatic Cancer Surveillance and Survival of High-Risk Individuals
  found_in:
  - Metastatic_Pancreatic_Adenocarcinoma-deep-research-falcon.md
  findings:
  - statement: ImportancePancreatic ductal adenocarcinoma (PDAC) is a deadly disease with increasing incidence.
    supporting_text: ImportancePancreatic ductal adenocarcinoma (PDAC) is a deadly disease with increasing incidence.
    evidence:
    - reference: DOI:10.1001/jamaoncol.2024.1930
      reference_title: Pancreatic Cancer Surveillance and Survival of High-Risk Individuals
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: ImportancePancreatic ductal adenocarcinoma (PDAC) is a deadly disease with increasing incidence.
      explanation: Deep research cited this publication as relevant literature for Metastatic Pancreatic Adenocarcinoma.
- reference: DOI:10.1038/s41467-023-40727-7
  title: Single cell transcriptomic analyses implicate an immunosuppressive tumor microenvironment in pancreatic cancer liver metastasis
  found_in:
  - Metastatic_Pancreatic_Adenocarcinoma-deep-research-falcon.md
  findings:
  - statement: Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease refractory to all targeted and immune therapies.
    supporting_text: Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease refractory to all targeted and immune therapies.
    evidence:
    - reference: DOI:10.1038/s41467-023-40727-7
      reference_title: Single cell transcriptomic analyses implicate an immunosuppressive tumor microenvironment in pancreatic cancer liver metastasis
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease refractory to all targeted and immune therapies.
      explanation: Deep research cited this publication as relevant literature for Metastatic Pancreatic Adenocarcinoma.
- reference: DOI:10.1038/s41591-024-03075-7
  title: Multi-parametric atlas of the pre-metastatic liver for prediction of metastatic outcome in early-stage pancreatic cancer
  found_in:
  - Metastatic_Pancreatic_Adenocarcinoma-deep-research-falcon.md
  findings:
  - statement: Multi-parametric atlas of the pre-metastatic liver for prediction of metastatic outcome in early-stage pancreatic cancer
    supporting_text: Multi-parametric atlas of the pre-metastatic liver for prediction of metastatic outcome in early-stage pancreatic cancer
- reference: DOI:10.1056/nejmoa1903387
  title: Maintenance Olaparib for Germline <i>BRCA</i> -Mutated Metastatic Pancreatic Cancer
  found_in:
  - Metastatic_Pancreatic_Adenocarcinoma-deep-research-falcon.md
  findings:
  - statement: Maintenance Olaparib for Germline <i>BRCA</i> -Mutated Metastatic Pancreatic Cancer
    supporting_text: Maintenance Olaparib for Germline <i>BRCA</i> -Mutated Metastatic Pancreatic Cancer
- reference: DOI:10.1136/jitc-2021-004485
  title: Detection of microsatellite instability-high (MSI-H) by liquid biopsy predicts robust and durable response to immunotherapy in patients with pancreatic cancer
  found_in:
  - Metastatic_Pancreatic_Adenocarcinoma-deep-research-falcon.md
  findings:
  - statement: Clinical trials reporting the robust antitumor activity of immune checkpoint inhibitors (ICIs) in microsatellite instability-high (MSI-H) solid tumors have used tissue-based testing to determine the MSI-H status.
    supporting_text: Clinical trials reporting the robust antitumor activity of immune checkpoint inhibitors (ICIs) in microsatellite instability-high (MSI-H) solid tumors have used tissue-based testing to determine the MSI-H status.
    evidence:
    - reference: DOI:10.1136/jitc-2021-004485
      reference_title: Detection of microsatellite instability-high (MSI-H) by liquid biopsy predicts robust and durable response to immunotherapy in patients with pancreatic cancer
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: Clinical trials reporting the robust antitumor activity of immune checkpoint inhibitors (ICIs) in microsatellite instability-high (MSI-H) solid tumors have used tissue-based testing to determine the MSI-H status.
      explanation: Deep research cited this publication as relevant literature for Metastatic Pancreatic Adenocarcinoma.
- reference: DOI:10.1186/s12943-024-02003-0
  title: Single-cell transcriptome analysis reveals subtype-specific clonal evolution and microenvironmental changes in liver metastasis of pancreatic adenocarcinoma and their clinical implications
  found_in:
  - Metastatic_Pancreatic_Adenocarcinoma-deep-research-falcon.md
  findings:
  - statement: Intratumoral heterogeneity (ITH) and tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) play important roles in tumor evolution and patient outcomes.
    supporting_text: Intratumoral heterogeneity (ITH) and tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) play important roles in tumor evolution and patient outcomes.
    evidence:
    - reference: DOI:10.1186/s12943-024-02003-0
      reference_title: Single-cell transcriptome analysis reveals subtype-specific clonal evolution and microenvironmental changes in liver metastasis of pancreatic adenocarcinoma and their clinical implications
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Intratumoral heterogeneity (ITH) and tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) play important roles in tumor evolution and patient outcomes.
      explanation: Deep research cited this publication as relevant literature for Metastatic Pancreatic Adenocarcinoma.
- reference: DOI:10.1200/jco.21.01604
  title: 'Overall Survival Results From the POLO Trial: A Phase III Study of Active Maintenance Olaparib Versus Placebo for Germline BRCA-Mutated Metastatic Pancreatic Cancer'
  found_in:
  - Metastatic_Pancreatic_Adenocarcinoma-deep-research-falcon.md
  findings:
  - statement: The phase III POLO study demonstrated significant progression-free survival (PFS) benefit for active olaparib maintenance therapy versus placebo for patients with metastatic pancreatic adenocarcinoma and a germline BRCA mutation.
    supporting_text: The phase III POLO study demonstrated significant progression-free survival (PFS) benefit for active olaparib maintenance therapy versus placebo for patients with metastatic pancreatic adenocarcinoma and a germline BRCA mutation.
    evidence:
    - reference: DOI:10.1200/jco.21.01604
      reference_title: 'Overall Survival Results From the POLO Trial: A Phase III Study of Active Maintenance Olaparib Versus Placebo for Germline BRCA-Mutated Metastatic Pancreatic Cancer'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The phase III POLO study demonstrated significant progression-free survival (PFS) benefit for active olaparib maintenance therapy versus placebo for patients with metastatic pancreatic adenocarcinoma and a germline BRCA mutation.
      explanation: Deep research cited this publication as relevant literature for Metastatic Pancreatic Adenocarcinoma.
- reference: DOI:10.12688/f1000research.21981.1
  title: Recent advances in the treatment of pancreatic cancer
  found_in:
  - Metastatic_Pancreatic_Adenocarcinoma-deep-research-falcon.md
  findings:
  - statement: Pancreatic ductal adenocarcinoma is one of the deadliest solid tumor malignancies and is projected to become a leading cause of cancer-related death in coming years.
    supporting_text: Pancreatic ductal adenocarcinoma is one of the deadliest solid tumor malignancies and is projected to become a leading cause of cancer-related death in coming years.
    evidence:
    - reference: DOI:10.12688/f1000research.21981.1
      reference_title: Recent advances in the treatment of pancreatic cancer
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Pancreatic ductal adenocarcinoma is one of the deadliest solid tumor malignancies and is projected to become a leading cause of cancer-related death in coming years.
      explanation: Deep research cited this publication as relevant literature for Metastatic Pancreatic Adenocarcinoma.
- reference: DOI:10.3322/caac.21820
  title: Cancer statistics, 2024
  found_in:
  - Metastatic_Pancreatic_Adenocarcinoma-deep-research-falcon.md
  findings:
  - statement: Cancer statistics, 2024
    supporting_text: Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population‐based cancer occurrence and outcomes using incidence data collected by central cancer registries (through 2020) and mortality data collected by the National Center for Health Statistics (through 2021).
    evidence:
    - reference: DOI:10.3322/caac.21820
      reference_title: Cancer statistics, 2024
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population‐based cancer occurrence and outcomes using incidence data collected by central cancer registries (through 2020) and mortality data collected by the National Center for Health Statistics (through 2021).
      explanation: Deep research cited this publication as relevant literature for Metastatic Pancreatic Adenocarcinoma.
- reference: DOI:10.3390/curroncol31090385
  title: Systemic Therapy for Metastatic Pancreatic Cancer—Current Landscape and Future Directions
  found_in:
  - Metastatic_Pancreatic_Adenocarcinoma-deep-research-falcon.md
  findings:
  - statement: Pancreatic ductal adenocarcinoma (PDAC) is a significant cause of cancer-associated mortality, with a rising global incidence.
    supporting_text: Pancreatic ductal adenocarcinoma (PDAC) is a significant cause of cancer-associated mortality, with a rising global incidence.
    evidence:
    - reference: DOI:10.3390/curroncol31090385
      reference_title: Systemic Therapy for Metastatic Pancreatic Cancer—Current Landscape and Future Directions
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Pancreatic ductal adenocarcinoma (PDAC) is a significant cause of cancer-associated mortality, with a rising global incidence.
      explanation: Deep research cited this publication as relevant literature for Metastatic Pancreatic Adenocarcinoma.
- reference: DOI:10.3390/onco5030037
  title: 'Pancreatic Cancer: Epidemiology, Risk Factors, and Prevention'
  found_in:
  - Metastatic_Pancreatic_Adenocarcinoma-deep-research-falcon.md
  findings:
  - statement: Pancreatic cancer (PC) is one of the most aggressive and lethal malignancies, mainly due to its late detection [...]
    supporting_text: Pancreatic cancer (PC) is one of the most aggressive and lethal malignancies, mainly due to its late detection [...]
    evidence:
    - reference: DOI:10.3390/onco5030037
      reference_title: 'Pancreatic Cancer: Epidemiology, Risk Factors, and Prevention'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Pancreatic cancer (PC) is one of the most aggressive and lethal malignancies, mainly due to its late detection [...]
      explanation: Deep research cited this publication as relevant literature for Metastatic Pancreatic Adenocarcinoma.
classifications:
  icdo_morphology:
    classification_value: Adenocarcinoma
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
review_notes: >-
  From the folded Metastatic_Pancreatic_Adenocarcinoma entry: its
  `environmental:` entry "Chronic pancreatitis" was removed and migrated to
  kb/comorbidities/com_Chronic_Pancreatitis__Pancreatic_Ductal_Adenocarcinoma.yaml
  (dismech#8296, dismech#8551). It is a disease in its own right rather than
  something external to the organism acting on it, so ECTO and XCO have no term
  that could bind it. All of its evidence was carried across.

📚

References & Deep Research

References

DOI:10.1146/annurev-pathmechdis-031621-024600

Tumor Microenvironment in Pancreatic Cancer Pathogenesis and Therapeutic Resistance

1 finding

PDAC has a prominent and spatially heterogeneous stromal microenvironment that meaningfully shapes treatment resistance.

DOI:10.1158/2159-8290.CD-23-0428

Senescence Defines a Distinct Subset of Myofibroblasts that Orchestrates Immunosuppression in Pancreatic Cancer

1 finding

Functionally distinct fibroblast states are part of the immunosuppressive circuitry of pancreatic cancer.

"Senescence defines a distinct subset of myofibroblasts that orchestrates immunosuppression in pancreatic cancer."

DOI:10.1001/jamaoncol.2024.1930

Pancreatic Cancer Surveillance and Survival of High-Risk Individuals

1 finding

ImportancePancreatic ductal adenocarcinoma (PDAC) is a deadly disease with increasing incidence.

"ImportancePancreatic ductal adenocarcinoma (PDAC) is a deadly disease with increasing incidence."

Show evidence (1 reference)

DOI:10.1001/jamaoncol.2024.1930 SUPPORT Human Clinical

"ImportancePancreatic ductal adenocarcinoma (PDAC) is a deadly disease with increasing incidence."

Deep research cited this publication as relevant literature for Metastatic Pancreatic Adenocarcinoma.

DOI:10.1038/s41467-023-40727-7

Single cell transcriptomic analyses implicate an immunosuppressive tumor microenvironment in pancreatic cancer liver metastasis

1 finding

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease refractory to all targeted and immune therapies.

"Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease refractory to all targeted and immune therapies."

Show evidence (1 reference)

DOI:10.1038/s41467-023-40727-7 SUPPORT Other

"Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease refractory to all targeted and immune therapies."

Deep research cited this publication as relevant literature for Metastatic Pancreatic Adenocarcinoma.

DOI:10.1038/s41591-024-03075-7

Multi-parametric atlas of the pre-metastatic liver for prediction of metastatic outcome in early-stage pancreatic cancer

1 finding

Multi-parametric atlas of the pre-metastatic liver for prediction of metastatic outcome in early-stage pancreatic cancer

"Multi-parametric atlas of the pre-metastatic liver for prediction of metastatic outcome in early-stage pancreatic cancer"

DOI:10.1056/nejmoa1903387

Maintenance Olaparib for Germline BRCA -Mutated Metastatic Pancreatic Cancer

1 finding

Maintenance Olaparib for Germline BRCA -Mutated Metastatic Pancreatic Cancer

"Maintenance Olaparib for Germline BRCA -Mutated Metastatic Pancreatic Cancer"

DOI:10.1136/jitc-2021-004485

Detection of microsatellite instability-high (MSI-H) by liquid biopsy predicts robust and durable response to immunotherapy in patients with pancreatic cancer

1 finding

Clinical trials reporting the robust antitumor activity of immune checkpoint inhibitors (ICIs) in microsatellite instability-high (MSI-H) solid tumors have used tissue-based testing to determine the MSI-H status.

"Clinical trials reporting the robust antitumor activity of immune checkpoint inhibitors (ICIs) in microsatellite instability-high (MSI-H) solid tumors have used tissue-based testing to determine the MSI-H status."

Show evidence (1 reference)

DOI:10.1136/jitc-2021-004485 SUPPORT Computational

Deep research cited this publication as relevant literature for Metastatic Pancreatic Adenocarcinoma.

DOI:10.1186/s12943-024-02003-0

Single-cell transcriptome analysis reveals subtype-specific clonal evolution and microenvironmental changes in liver metastasis of pancreatic adenocarcinoma and their clinical implications

1 finding

Intratumoral heterogeneity (ITH) and tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) play important roles in tumor evolution and patient outcomes.

"Intratumoral heterogeneity (ITH) and tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) play important roles in tumor evolution and patient outcomes."

Show evidence (1 reference)

DOI:10.1186/s12943-024-02003-0 SUPPORT Human Clinical

"Intratumoral heterogeneity (ITH) and tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) play important roles in tumor evolution and patient outcomes."

Deep research cited this publication as relevant literature for Metastatic Pancreatic Adenocarcinoma.

DOI:10.1200/jco.21.01604

Overall Survival Results From the POLO Trial: A Phase III Study of Active Maintenance Olaparib Versus Placebo for Germline BRCA-Mutated Metastatic Pancreatic Cancer

1 finding

The phase III POLO study demonstrated significant progression-free survival (PFS) benefit for active olaparib maintenance therapy versus placebo for patients with metastatic pancreatic adenocarcinoma and a germline BRCA mutation.

Show evidence (1 reference)

DOI:10.1200/jco.21.01604 SUPPORT Human Clinical

Deep research cited this publication as relevant literature for Metastatic Pancreatic Adenocarcinoma.

DOI:10.12688/f1000research.21981.1

Recent advances in the treatment of pancreatic cancer

1 finding

Pancreatic ductal adenocarcinoma is one of the deadliest solid tumor malignancies and is projected to become a leading cause of cancer-related death in coming years.

"Pancreatic ductal adenocarcinoma is one of the deadliest solid tumor malignancies and is projected to become a leading cause of cancer-related death in coming years."

Show evidence (1 reference)

DOI:10.12688/f1000research.21981.1 SUPPORT Human Clinical

"Pancreatic ductal adenocarcinoma is one of the deadliest solid tumor malignancies and is projected to become a leading cause of cancer-related death in coming years."

Deep research cited this publication as relevant literature for Metastatic Pancreatic Adenocarcinoma.

DOI:10.3322/caac.21820

Cancer statistics, 2024

1 finding

Cancer statistics, 2024

"Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population‐based cancer occurrence and outcomes using incidence data collected by central cancer registries (through 2020) and mortality data..."

Show evidence (1 reference)

DOI:10.3322/caac.21820 SUPPORT Human Clinical

Deep research cited this publication as relevant literature for Metastatic Pancreatic Adenocarcinoma.

DOI:10.3390/curroncol31090385

Systemic Therapy for Metastatic Pancreatic Cancer—Current Landscape and Future Directions

1 finding

Pancreatic ductal adenocarcinoma (PDAC) is a significant cause of cancer-associated mortality, with a rising global incidence.

"Pancreatic ductal adenocarcinoma (PDAC) is a significant cause of cancer-associated mortality, with a rising global incidence."

Show evidence (1 reference)

DOI:10.3390/curroncol31090385 SUPPORT Human Clinical

"Pancreatic ductal adenocarcinoma (PDAC) is a significant cause of cancer-associated mortality, with a rising global incidence."

Deep research cited this publication as relevant literature for Metastatic Pancreatic Adenocarcinoma.

DOI:10.3390/onco5030037

Pancreatic Cancer: Epidemiology, Risk Factors, and Prevention

1 finding

Pancreatic cancer (PC) is one of the most aggressive and lethal malignancies, mainly due to its late detection [...]

"Pancreatic cancer (PC) is one of the most aggressive and lethal malignancies, mainly due to its late detection [...]"

Show evidence (1 reference)

DOI:10.3390/onco5030037 SUPPORT Human Clinical

"Pancreatic cancer (PC) is one of the most aggressive and lethal malignancies, mainly due to its late detection [...]"

Deep research cited this publication as relevant literature for Metastatic Pancreatic Adenocarcinoma.

Deep Research

Falcon ▸

Disease Pathophysiology Research Template

Edison Scientific Literature 44 citations 2026-03-06T03:51:21.797267

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Pathophysiology Research Template

Target Disease

Disease Name: Pancreatic Ductal Adenocarcinoma
MONDO ID: (if available)
Category: Solid Tumor

Research Objectives

Please provide a comprehensive research report on the pathophysiology of Pancreatic Ductal Adenocarcinoma. Focus on the molecular and cellular mechanisms underlying disease progression.

Required Information

1. Core Pathophysiology

What are the primary pathophysiological mechanisms?
What molecular pathways are dysregulated?
What cellular processes are affected?

2. Key Molecular Players

Genes/Proteins: Which genes are causally involved or implicated?
Chemical Entities: What metabolites, drugs, or small molecules are relevant?
Cell Types: Which cell types are primarily affected?
Anatomical Locations: Which tissues/organs are involved?

3. Biological Processes (for GO annotation)

What biological processes (GO terms) are disrupted?
Consider: signaling pathways, metabolic processes, cellular responses, transport, etc.

4. Cellular Components

Where in the cell do key processes occur?
Consider: organelles, membrane compartments, extracellular space, etc.

5. Disease Progression

What is the sequence of events from initial trigger to clinical manifestation?
Are there distinct stages or phases?

6. Phenotypic Manifestations

What are the key clinical phenotypes?
How do they relate to the underlying mechanisms?

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic claims
Prioritize recent reviews and landmark papers
Include direct quotes where possible to support key statements

Output Format

Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs

Comprehensive Research Report: Pathophysiology of Pancreatic Ductal Adenocarcinoma (PDAC)

Target disease and identifiers

Disease: Pancreatic ductal adenocarcinoma (PDAC)
MONDO ID: MONDO:0005184 (Open Targets disease record for “pancreatic ductal adenocarcinoma”) (vitorakis2024precisiontargetingstrategies pages 2-3)

1) Key concepts and definitions (current understanding)

1.1 Definition and core biological framing

PDAC is a malignant epithelial tumor arising from the pancreatic ductal system (or ductal-like cells derived from acinar reprogramming), characterized by (i) near-universal oncogenic KRAS pathway activation, (ii) frequent inactivation of a small set of core tumor suppressors, and (iii) a uniquely fibro-inflammatory, desmoplastic tumor microenvironment (TME) that strongly constrains perfusion, immune infiltration, and drug delivery (sherman2023tumormicroenvironmentin pages 4-6, finan2024challengesandopportunities pages 1-2).

A key modern concept is that PDAC is not purely a cancer-cell autonomous disease; rather, it is an ecosystem-level disease in which non-malignant stromal and immune compartments co-evolve with the neoplastic epithelium and meaningfully drive progression and therapy resistance (finan2024challengesandopportunities pages 1-2, sherman2023tumormicroenvironmentin pages 4-6).

1.2 Precursor lesions and progression model

Two major precursor lesion routes dominate contemporary models: - PanIN lesions account for ~85–90% of PDAC and - IPMN lesions account for ~10–15% (linehan2024targetingkrasmutations pages 2-4, terza2024transcriptionalandspatial pages 24-26).

These lesions acquire additional genetic/epigenetic alterations over time, culminating in invasive carcinoma with metastatic competence (graham2024fromprecursorto pages 8-9, sherman2023tumormicroenvironmentin pages 4-6).

2) Core pathophysiology (molecular and cellular mechanisms)

2.1 Cell-intrinsic oncogenic programs

KRAS-centered oncogenic signaling

KRAS is the dominant initiating oncogene in PDAC. Multiple recent reviews converge on the point that KRAS mutation is an early event, detectable in low-grade precursor lesions and present in the vast majority of PDAC tumors (linehan2024targetingkrasmutations pages 2-4).

Mechanistically, KRAS engages canonical downstream cascades: - MAPK/RAF–MEK–ERK: “Activated KRAS ignites phosphorylation of RAF and subsequently… ERK 1 and 2” (linehan2024targetingkrasmutations pages 2-4). - PI3K–AKT: “Activated PI3K phosphorylates… PIP3 promoting AKT phosphorylation” (linehan2024targetingkrasmutations pages 2-4).

These pathways support proliferation, survival, and transcriptional programs that enable malignant progression and plasticity, particularly in inflammatory contexts (sherman2023tumormicroenvironmentin pages 4-6, hashimoto2024plasticityandtumor pages 3-5).

Core tumor suppressor losses and malignant progression

Multiple 2024 syntheses summarize the canonical PDAC “four-driver” framework and provide quantitative prevalence estimates: - “The driver genes in PDAC are four: KRAS…SMAD4…CDKN2A/p16…TP53” and “KRAS mutations are prevalent in 80–95% of PDACs” (vitorakis2024precisiontargetingstrategies pages 2-3). - CDKN2A/p16 inactivation occurs in “more than 90%” of PDAC (vitorakis2024precisiontargetingstrategies pages 2-3, reshkin2024geneticsignatureof pages 3-4). - TP53 disruption occurs in about “six out of ten” tumors (~60%) (vitorakis2024precisiontargetingstrategies pages 2-3) and is also summarized as common in progression (graham2024fromprecursorto pages 8-9). - SMAD4 loss is “prevalent in half of the cases” (~50%) (vitorakis2024precisiontargetingstrategies pages 2-3, reshkin2024geneticsignatureof pages 3-4).

Recent precursor-focused review work (2024) emphasizes the dual role of intrinsic alterations and extrinsic cues (inflammation, fibroblast activation, immune modulation) in driving PanIN progression to PDAC (graham2024fromprecursorto pages 8-9).

2.2 Cell-extrinsic programs: the desmoplastic, immunosuppressive ecosystem

Desmoplasia and ECM barriers

PDAC is strongly defined by extensive fibrosis and ECM deposition. A recent 2024 review states that PDAC stroma “can make up… as much as 90% of its volume” (vitorakis2024precisiontargetingstrategies pages 6-8). In another 2024 review, PDAC is described as an “ecosystem, with up to 80% of the mass consisting of nontumor stromal cells and extracellular matrix (ECM)” (finan2024challengesandopportunities pages 1-2).

The ECM is biochemically dominated by: - “hyaluronic acid (HA)” and - “collagens type I, III, and IV” (vitorakis2024precisiontargetingstrategies pages 6-8).

These components are not merely structural: “lower levels of stromal HA and collagen are linked to improved survival rates” in observational analyses summarized in 2024 (vitorakis2024precisiontargetingstrategies pages 6-8). This provides a mechanistic rationale for ECM/HA-degrading approaches (see Applications).

CAF heterogeneity and immunoregulatory roles

A major advance in 2023–2024 is the consolidation of CAF heterogeneity into functionally distinct subsets. Belle et al. (Cancer Discovery; final publication July 1, 2024; DOI: 10.1158/2159-8290.CD-23-0428; URL: https://doi.org/10.1158/2159-8290.CD-23-0428) describe PDAC TME as “dense collagen-rich extracellular matrix (ECM) harboring an abundance of carcinoma-associated fibroblasts (CAFs)” and note that PDAC has a “5-year survival rate of 12%” (belle2024senescencedefinesa pages 1-3).

They also provide a clear scRNA-seq-derived CAF taxonomy: - “Myofibroblastic CAFs (myCAFs) are enriched for ECM factors… (Acta2); Inflammatory CAFs (iCAF) are enriched for cytokines… like Il6; Antigen-presenting CAFs (apCAFs) express Cd74 and MHCII genes” (belle2024senescencedefinesa pages 1-3).

Critically, CAFs are not neutral; CAF subsets can directly impose immune exclusion/suppression. Belle et al. summarize that “FAP+ CAFs recruit immunosuppressive macrophages and spatially exclude CD8+ T cells… through CXCL12/SDF1-CXCR4 sequestration” (belle2024senescencedefinesa pages 1-3). This mechanism is a central “pathophysiology-to-therapy” bridge in PDAC.

In the same work, senescence is elevated as a stromal state that shapes immunity and treatment response: “Senescence defines a distinct subset of myofibroblasts that… orchestrates immunosuppression in pancreatic cancer” (belle2024senescencedefinesa pages 1-3). Visual evidence for CAF subset structure and SenCAF-associated immunosuppressive circuitry is shown in Belle et al. figures (belle2024senescencedefinesa media 67220de1, belle2024senescencedefinesa media 1506df91).

Immunosuppressive leukocyte networks

A 2024 clinical/translational review lists major checkpoint regulators of CD8 T cells: “PD-1… CTLA-4… TIM-3… TIGIT” (finan2024challengesandopportunities pages 1-2). It also provides direct evidence that “Treg cells are recruited to tumors via… CCL2 and CCL5” and then suppress cytotoxic immunity through “IL-10, TGF-b, CTLA-4, granzyme B” (finan2024challengesandopportunities pages 1-2).

These immune suppressive programs are reinforced by oncogenic KRAS signaling and by physical/ecological restrictions imposed by the ECM-rich stroma (sherman2023tumormicroenvironmentin pages 4-6, finan2024challengesandopportunities pages 1-2).

2.3 Metabolic rewiring and immune–metabolic coupling

KRAS-driven glycolysis and hypoxia adaptation

Bonilla et al. (JCI Insight; Aug 2024; DOI: 10.1172/jci.insight.180114; URL: https://doi.org/10.1172/jci.insight.180114) compile mechanistic evidence that oncogenic KRAS upregulates glycolysis programs in PDAC (e.g., “HK1/2… PFK1… LDHA”), increases glucose uptake via PI3K-Akt–mediated GLUT1 expression, and increases lactate generation (bonilla2024metaboliclandscapeof pages 21-25).

Hashimoto & Hashimoto (Cancers; Dec 2024; DOI: 10.3390/cancers16234094; URL: https://doi.org/10.3390/cancers16234094) further emphasize hypoxia-driven metabolic switching: hypoxia/HIF-1α induces “GLUT1, LDHA and MCT4,” shifting from OXPHOS to glycolysis and exporting lactate; the resulting “acidic TME… inhibits CD8+ T-cells and NK cells” and promotes immunosuppressive macrophage states (hashimoto2024plasticityandtumor pages 8-9).

Glutamine dependence and nutrient scavenging

Recent reviews highlight PDAC “glutamine addiction” and scavenging programs. Hashimoto & Hashimoto note glutamine’s role in supporting the TCA cycle and redox, and report that glutaminase inhibition (BPTES) suppresses PDAC proliferation in cited work (hashimoto2024plasticityandtumor pages 8-9, hashimoto2024plasticityandtumor pages 9-10).

Both Bonilla et al. and Hashimoto & Hashimoto emphasize autophagy and macropinocytosis as nutrient acquisition strategies in KRAS-mutant PDAC (bonilla2024metaboliclandscapeof pages 21-25, hashimoto2024plasticityandtumor pages 10-12).

Autophagy as immune evasion

Gautam et al. (Molecular Cancer; Jul 2023; DOI: 10.1186/s12943-023-01813-y; URL: https://doi.org/10.1186/s12943-023-01813-y) provide a specific mechanistic immune-evasion statement: “constitutively active KRasG12D regulates autophagy-induced MHCI downregulation” (gautam2023molecularandmetabolic pages 1-2). This connects oncogenic metabolism/trafficking to reduced antigen presentation.

3) Key molecular players, cell types, anatomical sites, and chemical entities

3.1 Genes/Proteins (HGNC; causality/implication)

Core driver set repeatedly emphasized in 2024 syntheses: - KRAS, TP53, CDKN2A, SMAD4 (vitorakis2024precisiontargetingstrategies pages 2-3, reshkin2024geneticsignatureof pages 3-4).

Additional mechanisms and mediators: - CXCL12–CXCR4 (CAF/PSC-mediated immune exclusion) (belle2024senescencedefinesa pages 1-3, vitorakis2024precisiontargetingstrategies pages 8-10). - Immune checkpoints: PD-1, CTLA-4, TIM-3, TIGIT (finan2024challengesandopportunities pages 1-2).

3.2 Chemical entities (metabolites / ECM)

Hyaluronic acid (HA), collagens (I/III/IV) as dominant ECM components (vitorakis2024precisiontargetingstrategies pages 6-8).
Lactate as a glycolytic end product shaping an acidic immunosuppressive microenvironment (hashimoto2024plasticityandtumor pages 8-9, bonilla2024metaboliclandscapeof pages 21-25).
Glutamine as a major carbon/nitrogen source enabling growth in nutrient-restricted settings (hashimoto2024plasticityandtumor pages 8-9, bonilla2024metaboliclandscapeof pages 21-25).

3.3 Cell types (CL-style)

CAF subsets: myCAF, iCAF, apCAF, plus senescent myCAF/SenCAF states (belle2024senescencedefinesa pages 1-3).
Immune suppressive populations: Tregs, TAMs, MDSCs (finan2024challengesandopportunities pages 1-2, linehan2024targetingkrasmutations pages 2-4).
Pancreatic stellate cells (PSCs) as major myofibroblast-like drivers of desmoplasia (vitorakis2024precisiontargetingstrategies pages 8-10).

3.4 Anatomical locations (UBERON-style)

Pancreas and pancreatic ductal system as the primary site; PanIN lesions form in pancreatic epithelium context (graham2024fromprecursorto pages 8-9, sherman2023tumormicroenvironmentin pages 4-6).
Liver as a major metastatic destination with distinct immune/metabolic niche properties (gautam2023molecularandmetabolic pages 1-2).

4) Biological processes (GO-style) and cellular components (GO-CC-style)

4.1 Disrupted biological processes

Representative GO-style processes supported by 2023–2024 evidence include: - Epithelial cell transformation / acinar-to-ductal metaplasia, linked to KRAS and inflammatory priming (sherman2023tumormicroenvironmentin pages 4-6, graham2024fromprecursorto pages 8-9). - Extracellular matrix organization / collagen fibril organization / desmoplastic reaction (vitorakis2024precisiontargetingstrategies pages 6-8, finan2024challengesandopportunities pages 1-2). - Immune evasion via checkpoint regulation and antigen presentation suppression (MHC-I downregulation) (finan2024challengesandopportunities pages 1-2, gautam2023molecularandmetabolic pages 1-2). - Aerobic glycolysis, lactate production/export, glutamine metabolism, autophagy, macropinocytosis (hashimoto2024plasticityandtumor pages 8-9, bonilla2024metaboliclandscapeof pages 21-25, hashimoto2024plasticityandtumor pages 10-12).

4.2 Key cellular components

Extracellular matrix (ECM): collagen-rich; HA-rich (belle2024senescencedefinesa pages 1-3, vitorakis2024precisiontargetingstrategies pages 6-8).
Autophagosome/lysosome system (autophagy-mediated immune escape and nutrient recycling) (gautam2023molecularandmetabolic pages 1-2, hashimoto2024plasticityandtumor pages 10-12).
MHC class I complex / cell surface antigen presentation machinery, functionally downregulated by KRAS-linked autophagy (gautam2023molecularandmetabolic pages 1-2).

5) Disease progression: sequence of events (trigger → clinical manifestations)

5.1 Initiation: genetic + inflammatory “two-lens” model

A central contemporary model is that KRAS mutation initiates neoplastic potential, but inflammation/pancreatitis-like microenvironmental cues collaborate with KRAS to enable PanIN formation and progression by bypassing intrinsic barriers such as senescence and by inducing transcriptional/epigenetic reprogramming (sherman2023tumormicroenvironmentin pages 4-6, graham2024fromprecursorto pages 8-9).

5.2 Pre-invasive lesions → invasive carcinoma

Precursor lesions (PanIN/IPMN) acquire sequential tumor suppressor alterations (CDKN2A, TP53, SMAD4) and additional chromosomal/epigenetic changes that coincide with rising dysplasia grade and invasive transition (graham2024fromprecursorto pages 8-9, reshkin2024geneticsignatureof pages 3-4).

5.3 Ecosystem maturation and therapy resistance

As PDAC develops, the stroma expands and diversifies, including CAF subsets and immunosuppressive leukocytes. This produces: - physical barriers (HA/collagen), - hypoxia and altered metabolite gradients, - immune exclusion (CXCL12/CXCR4), and - checkpoint-mediated T cell dysfunction (belle2024senescencedefinesa pages 1-3, finan2024challengesandopportunities pages 1-2).

5.4 Metastasis and pre-metastatic niche conditioning

A 2023 metastatic immunosuppression review describes dissemination “following chemokine and exosomal guidance” to organ-specific pre-metastatic niches (PMNs) composed of resident cells, fibroblasts, and suppressive immune cells such as “metastasis-associated macrophages, neutrophils, and myeloid-derived suppressor cells” (gautam2023molecularandmetabolic pages 1-2).

6) Phenotypic manifestations and clinical correlates

6.1 Survival and stage-at-diagnosis statistics (recent sources)

Recent 2024 sources report consistently poor outcomes: - 5-year survival ~13% (Finan et al., published Dec 18, 2024; DOI: 10.1200/OA-24-00050; URL: https://doi.org/10.1200/OA-24-00050) (finan2024challengesandopportunities pages 1-2). - “only… about 13% of PDAC patients does the overall survival exceed 5 years” (Poyia et al., Sep 2024; DOI: 10.3390/ijms25179555; URL: https://doi.org/10.3390/ijms25179555) (poyia2024theroleof pages 1-2). - Belle et al. cite 5-year survival 12% (Cancer Discovery 2024; DOI: 10.1158/2159-8290.CD-23-0428; URL: https://doi.org/10.1158/2159-8290.CD-23-0428) (belle2024senescencedefinesa pages 1-3).

6.2 Mutation frequencies and clinical phenotypes

KRAS mutation frequency is reported as 80–95% (vitorakis2024precisiontargetingstrategies pages 2-3) and also summarized as ~90% (poyia2024theroleof pages 1-2).
Tumor suppressor inactivation estimates vary by cohort and review: “50–80% have inactivating mutations in TP53, CDKN2A, and SMAD4” (poyia2024theroleof pages 1-2), whereas other 2024 compilations provide ~60% TP53 and ~50% SMAD4 (vitorakis2024precisiontargetingstrategies pages 2-3).

6.3 TME-driven phenotypes

The dense, HA/collagen-rich stroma produces hypoperfusion, high interstitial pressure, and immune exclusion, which clinically correspond to: - chemoresistance, - immunotherapy resistance (“cold” tumors), and - aggressive local invasion and early metastatic spread (finan2024challengesandopportunities pages 1-2, vitorakis2024precisiontargetingstrategies pages 6-8).

7) Recent developments and latest research (prioritizing 2023–2024)

7.1 CAF subset refinement, senescence biology, and immunosuppression (2024)

A key 2024 advance is the identification of senescent myofibroblastic CAFs (SenCAFs) and evidence that senescent stromal depletion can “relieve immune suppression by macrophages, delay tumor progression and increase responsiveness to chemotherapy” in models (belle2024senescencedefinesa pages 1-3). The associated figures provide a mechanistic schematic for SenCAF→macrophage→CD8 T cell dysfunction (belle2024senescencedefinesa media 1506df91) and CAF subset structure (belle2024senescencedefinesa media 67220de1).

7.2 Ecosystem quantification and CAF lineages (2024)

Finan et al. quantify the stromal burden (up to 80% mass) and emphasize that CAFs are heterogeneous in both origin and function, with only “10%–15% of CAFs… derived from PSCs” (finan2024challengesandopportunities pages 1-2). They also note dynamic interconversion between iCAFs and myCAFs (finan2024challengesandopportunities pages 1-2).

7.3 Metabolic ecosystem mapping and immune metabolism (2024)

Bonilla et al. (Aug 2024) synthesize mechanistic evidence linking KRAS to glycolytic reprogramming, glutamine rewiring, autophagy/macropinocytosis, and immune dysfunction via nutrient competition (bonilla2024metaboliclandscapeof pages 21-25). Hashimoto & Hashimoto (Dec 2024) emphasize HIF-1α-driven lactate export and its immune suppressive consequences in acidic PDAC microenvironments (hashimoto2024plasticityandtumor pages 8-9).

7.4 Metastatic immunometabolic “hot spots” (2023)

A 2023 metastatic PDAC review emphasizes that metastatic immune ecosystems differ from primary tumors in “composition, functionality, and metabolism,” and formalizes PMN formation via “chemokine and exosomal guidance” (gautam2023molecularandmetabolic pages 1-2).

8) Current applications and real-world implementations

8.1 Stromal/ECM targeting (hyaluronan and related strategies)

A 2024 ASCO/clinical review summarizes ECM/hyaluronan-targeting efforts including PEGPH20 (hyaluronidase) in combinations: - HALO 109-301, - PEGPH20 + pembrolizumab (PCRT16-001), - MORPHEUS platform (atezolizumab + PEGPH20) (finan2024challengesandopportunities pages 20-21).

These efforts are directly motivated by the pathophysiology that HA impairs vascular function and drug delivery in PDAC (finan2024challengesandopportunities pages 20-21, vitorakis2024precisiontargetingstrategies pages 6-8).

8.2 Immune targeting beyond PD-1/CTLA-4 (adenosine/CD73 axis)

A 2024 trial compendium highlights multiple trials targeting immunosuppressive adenosine biology, including: - A2A/A2B antagonists (NCT04580485), - anti-CD73 strategies (e.g., NCT04989387), and CD73 small-molecule inhibition with checkpoint blockade (zimberelimab + quemliclustat; NCT05688215) (do2024theroadahead pages 3-4).

8.3 Antigen/vaccine approaches including KRAS-directed vaccines (2024)

A 2024 review catalogs KRAS-directed vaccine efforts, including ELI-002 (NCT04853017) containing “G12D and G12R mutant KRAS peptides” (do2024theroadahead pages 6-8).

8.4 Imaging/biomarkers that operationalize stromal biology: 68Ga-FAPI PET

A 2024 CAF-focused review describes FAP as a CAF marker leveraged for clinical imaging and notes that Gallium-68 FAP inhibitor (68Ga-FAPI) PET/CT has “promising diagnostic sensitivity and specificity” with low non-tumoral uptake and expected intensive uptake in PDAC (saudeconde2024cancerassociatedfibroblastsin pages 1-2). This is a direct real-world implementation grounded in PDAC’s CAF-rich desmoplasia.

9) Expert opinions and analysis (authoritative sources)

9.1 Why PDAC resists therapy

The 2024 ASCO review frames PDAC’s poor response as partially attributable to the “dense stroma and heterogeneous tumor microenvironment (TME)” and notes that many stromal-targeting trials “have failed to improve overall patient outcomes” when translated clinically, motivating combination and stratification strategies (finan2024challengesandopportunities pages 1-2).

9.2 Why CAF targeting is complex

Belle et al. explicitly note contradictory outcomes in CAF depletion studies and interpret this as evidence of “underappreciated phenotypic heterogeneity of CAFs,” arguing for subset- and state-specific targeting rather than global stromal ablation (belle2024senescencedefinesa pages 1-3).

10) Evidence-driven structured content for knowledge-base population

Mechanism / Process	Key Molecular Players	Key Cell Types	Dysregulated Pathways	Key Findings & Evidence	Key Sources (2023-2024)
KRAS-Driven Initiation & Progression	KRAS (G12D/V/R), IL-33	Acinar cells, Ductal cells	MAPK/ERK, PI3K-AKT, Ral	KRAS mutations (>90% of PDAC) are the initiating event, driving acinar-to-ductal metaplasia (ADM) and PanINs; requires inflammation (e.g., IL-33) to bypass senescence and amplify transformation.	(vitorakis2024precisiontargetingstrategies pages 2-3, linehan2024targetingkrasmutations pages 2-4, graham2024fromprecursorto pages 8-9, sherman2023tumormicroenvironmentin pages 4-6)
Tumor Suppressor Inactivation	CDKN2A (p16), TP53, SMAD4, BRCA2	Neoplastic epithelial cells	Cell cycle (G1/S), DNA repair, TGF-β	Progressive accumulation: CDKN2A lost early (>90%); TP53 (~60-70%) and SMAD4 (~50%) lost in high-grade PanIN/invasive disease, driving genomic instability and malignancy.	(vitorakis2024precisiontargetingstrategies pages 2-3, linehan2024targetingkrasmutations pages 2-4, graham2024fromprecursorto pages 8-9, reshkin2024geneticsignatureof pages 3-4)
Desmoplasia & ECM Barriers	Hyaluronan (HA), Collagens (I, III, IV), Fibronectin	PSCs (Pancreatic Stellate Cells), CAFs	Hedgehog (SHH), TGF-β	Dense stroma (up to 90% tumor volume) creates high interstitial pressure, hypoxia, and a physical barrier to drugs/immune cells; driven by PSC activation.	(vitorakis2024precisiontargetingstrategies pages 6-8, finan2024challengesandopportunities pages 1-2, saudeconde2024cancerassociatedfibroblastsin pages 1-2, vitorakis2024precisiontargetingstrategies pages 8-10)
CAF Heterogeneity & Function	FAP, α-SMA, IL-6, MHC-II, CXCL12	myCAF (myofibroblastic), iCAF (inflammatory), apCAF, SenCAF	IL-1/JAK-STAT, TGF-β, CXCL12/CXCR4	Distinct subsets: myCAFs (ECM-producing, α-SMA high); iCAFs (IL-6 high); apCAF (antigen-presenting); SenCAF (senescent) accumulate with progression. FAP+ CAFs exclude CD8+ T cells via CXCL12.	(belle2024senescencedefinesa pages 1-3, finan2024challengesandopportunities pages 1-2, erreni2024depictingthecellular pages 12-13)
Immune Evasion & Suppression	PD-L1, CTLA-4, CCL2, CCL5, Galectin-1	Tregs, TAMs (M2-like), MDSCs	Immune checkpoint, Chemokine signaling	"Cold" tumor phenotype; KRAS-driven GM-CSF/chemokines recruit MDSCs/Tregs. Autophagy downregulates MHC-I. TAMs support fibrosis and suppress CTLs.	(gautam2023molecularandmetabolic pages 1-2, belle2024senescencedefinesa pages 1-3, finan2024challengesandopportunities pages 1-2, finan2024challengesandopportunities pages 20-21)
Metabolic Rewiring	GLUT1, LDHA, Glutaminase (GLS)	PDAC cells, CAFs	Glycolysis (Warburg), Glutaminolysis, Mevalonate	KRAS drives glucose uptake/glycolysis and "glutamine addiction." Nutrient scavenging via macropinocytosis and autophagy (recycling) supports growth in nutrient-poor TME.	(hashimoto2024plasticityandtumor pages 8-9, hashimoto2024plasticityandtumor pages 9-10, bonilla2024metaboliclandscapeof pages 21-25)
TME Metabolic Crosstalk	Lactate, Lipids, Cholesterol	Tumor cells, Immune cells	HIF-1α (Hypoxia), mTORC1	Hypoxia/HIF-1α shifts cells to glycolysis, exporting lactate which acidifies TME and suppresses T cells. TAMs/stroma engage in lipid/cholesterol exchange with tumor cells.	(hashimoto2024plasticityandtumor pages 8-9, bonilla2024metaboliclandscapeof pages 25-29, bonilla2024metaboliclandscapeof pages 21-25, bonilla2024metaboliclandscapeof pages 17-21)
Metastatic Niche (PMN)	Exosomes, Chemokines	Metastasis-Associated Macrophages (MAMs)	EMT, Exosomal guidance	Primary tumors secrete factors/exosomes to prime pre-metastatic niches (PMNs) in liver/lung; metastatic cells have distinct metabolic/immune profiles from primary.	(gautam2023molecularandmetabolic pages 1-2, sherman2023tumormicroenvironmentin pages 4-6)

Table: A structured summary of the primary pathophysiological mechanisms in Pancreatic Ductal Adenocarcinoma, highlighting the interplay between genetic drivers, the tumor microenvironment (TME), and metabolic alterations as described in 2023-2024 literature.

Entity Type	Identifier / Name	Role in PDAC	Evidence Snippet / Mechanism	Supporting Sources (2023-2024)
Gene (HGNC)	KRAS	Driver (Initiation)	"KRAS mutations are prevalent in 80–95% of PDACs" driving initiation/ADM.	(vitorakis2024precisiontargetingstrategies pages 2-3, linehan2024targetingkrasmutations pages 2-4)
Gene (HGNC)	TP53	Tumor Suppressor	Inactivation in ~60-70% contributes to genomic instability in progression.	(vitorakis2024precisiontargetingstrategies pages 2-3, reshkin2024geneticsignatureof pages 3-4)
Gene (HGNC)	CDKN2A (p16)	Tumor Suppressor	"CDKN2A/p16 deactivation... in more than 90% of PDACs."	(vitorakis2024precisiontargetingstrategies pages 2-3)
Gene (HGNC)	SMAD4	Tumor Suppressor	Loss associated with progression; "prevalent in half of the cases."	(vitorakis2024precisiontargetingstrategies pages 2-3, graham2024fromprecursorto pages 8-9)
Cell Type (CL)	myCAF	Stromal Remodeling	"aSMAhigh, ECM-producing myofibroblastic CAFs"; generate collagen barrier.	(belle2024senescencedefinesa pages 1-3, finan2024challengesandopportunities pages 1-2)
Cell Type (CL)	iCAF	Inflammation	"IL-6high inflammatory CAFs"; secrete cytokines, support immunosuppression.	(belle2024senescencedefinesa pages 1-3, finan2024challengesandopportunities pages 1-2)
Cell Type (CL)	SenCAF	Immunosuppression	"Senescent myofibroblastic CAFs... orchestrate immunosuppression" via CXCL12.	(belle2024senescencedefinesa pages 1-3)
Cell Type (CL)	PSC	Progenitor	"Pancreatic stellate cells... key myofibroblast-like drivers of desmoplasia."	(vitorakis2024precisiontargetingstrategies pages 8-10, finan2024challengesandopportunities pages 1-2)
Bio Process (GO)	Glycolysis	Metabolic Rewiring	KRAS upregulates GLUT1/LDHA; "hypoxia... enforces glycolytic programming."	(hashimoto2024plasticityandtumor pages 8-9, bonilla2024metaboliclandscapeof pages 21-25)
Bio Process (GO)	Macropinocytosis	Nutrient Scavenging	"KRAS-driven macropinocytosis supplies free amino acids" (scavenging).	(hashimoto2024plasticityandtumor pages 8-9, hashimoto2024plasticityandtumor pages 10-12)
Bio Process (GO)	Autophagy	Survival & Evasion	Recycles nutrients; "regulates autophagy-induced MHCI downregulation" (evasion).	(gautam2023molecularandmetabolic pages 1-2, hashimoto2024plasticityandtumor pages 10-12)
Chemical (ChEBI)	Hyaluronan (HA)	ECM Component	"Predominant component" of stroma; raises interstitial pressure, impairs drugs.	(vitorakis2024precisiontargetingstrategies pages 6-8, finan2024challengesandopportunities pages 20-21)
Chemical (ChEBI)	Lactate	Metabolite	Exported by tumor cells; "creates an acidic TME that inhibits cytotoxic CD8+."	(hashimoto2024plasticityandtumor pages 8-9, bonilla2024metaboliclandscapeof pages 21-25)
Chemical (ChEBI)	Glutamine	Metabolite	"Glutamine addiction"; fuels TCA cycle and lipid synthesis via reductive path.	(hashimoto2024plasticityandtumor pages 8-9, hashimoto2024plasticityandtumor pages 9-10)
Anatomy (UBERON)	Liver	Metastatic Site	Most common metastatic site; "metastatic immune microenvironment differs from primary."	(gautam2023molecularandmetabolic pages 1-2)

Table: A structured table mapping key PDAC entities (genes, cell types, processes, chemicals) to their specific pathophysiological roles and evidence, suitable for disease knowledge base integration.

11) Visual evidence (figures/tables)

Belle et al. 2024 provides figure evidence for CAF subset structure and SenCAF-associated immunosuppressive circuitry (CAF clusters/markers; schematic of SenCAF→macrophage→CD8 dysfunction) (belle2024senescencedefinesa media 67220de1, belle2024senescencedefinesa media 1506df91).

12) Evidence items (PMID notes)

Where possible, PMID was requested; however, many retrieved full texts and excerpts provided DOIs/URLs without explicit PMID strings in the extracted passages. A notable exception is that Open Targets evidence lists historical PubMed IDs for KRAS–PDAC associations (e.g., PMID: 29658583) but these are not the primary 2023–2024 mechanistic sources extracted here (vitorakis2024precisiontargetingstrategies pages 2-3). For the core 2023–2024 mechanistic statements, this report therefore cites DOI/URL + publication date and the exact extracted text evidence.

References

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(hashimoto2024plasticityandtumor pages 3-5): Ari Hashimoto and Shigeru Hashimoto. Plasticity and tumor microenvironment in pancreatic cancer: genetic, metabolic, and immune perspectives. Cancers, 16:4094, Dec 2024. URL: https://doi.org/10.3390/cancers16234094, doi:10.3390/cancers16234094. This article has 7 citations.
(reshkin2024geneticsignatureof pages 3-4): Stephan J. Reshkin, Rosa Angela Cardone, and Tomas Koltai. Genetic signature of human pancreatic cancer and personalized targeting. Cells, 13:602, Mar 2024. URL: https://doi.org/10.3390/cells13070602, doi:10.3390/cells13070602. This article has 10 citations.
(vitorakis2024precisiontargetingstrategies pages 6-8): Nikolaos Vitorakis, Antonios N. Gargalionis, Kostas A. Papavassiliou, Christos Adamopoulos, and Athanasios G. Papavassiliou. Precision targeting strategies in pancreatic cancer: the role of tumor microenvironment. Cancers, 16:2876, Aug 2024. URL: https://doi.org/10.3390/cancers16162876, doi:10.3390/cancers16162876. This article has 17 citations.
(belle2024senescencedefinesa pages 1-3): Jad I. Belle, Devashish Sen, John M. Baer, Xiuting Liu, Varintra E. Lander, Jiayu Ye, Blake E. Sells, Brett L. Knolhoff, Ahmad Faiz, Liang-I Kang, Guhan Qian, Ryan C. Fields, Li Ding, Hyun Kim, Paolo P. Provenzano, Sheila A. Stewart, and David G. DeNardo. Senescence defines a distinct subset of myofibroblasts that orchestrates immunosuppression in pancreatic cancer. Cancer discovery, 14:1324-1355, Apr 2024. URL: https://doi.org/10.1158/2159-8290.cd-23-0428, doi:10.1158/2159-8290.cd-23-0428. This article has 82 citations and is from a highest quality peer-reviewed journal.
(belle2024senescencedefinesa media 67220de1): Jad I. Belle, Devashish Sen, John M. Baer, Xiuting Liu, Varintra E. Lander, Jiayu Ye, Blake E. Sells, Brett L. Knolhoff, Ahmad Faiz, Liang-I Kang, Guhan Qian, Ryan C. Fields, Li Ding, Hyun Kim, Paolo P. Provenzano, Sheila A. Stewart, and David G. DeNardo. Senescence defines a distinct subset of myofibroblasts that orchestrates immunosuppression in pancreatic cancer. Cancer discovery, 14:1324-1355, Apr 2024. URL: https://doi.org/10.1158/2159-8290.cd-23-0428, doi:10.1158/2159-8290.cd-23-0428. This article has 82 citations and is from a highest quality peer-reviewed journal.
(belle2024senescencedefinesa media 1506df91): Jad I. Belle, Devashish Sen, John M. Baer, Xiuting Liu, Varintra E. Lander, Jiayu Ye, Blake E. Sells, Brett L. Knolhoff, Ahmad Faiz, Liang-I Kang, Guhan Qian, Ryan C. Fields, Li Ding, Hyun Kim, Paolo P. Provenzano, Sheila A. Stewart, and David G. DeNardo. Senescence defines a distinct subset of myofibroblasts that orchestrates immunosuppression in pancreatic cancer. Cancer discovery, 14:1324-1355, Apr 2024. URL: https://doi.org/10.1158/2159-8290.cd-23-0428, doi:10.1158/2159-8290.cd-23-0428. This article has 82 citations and is from a highest quality peer-reviewed journal.
(bonilla2024metaboliclandscapeof pages 21-25): Monica E. Bonilla, Megan D. Radyk, Matthew D. Perricone, Ahmed M. Elhossiny, Alexis C. Harold, Paola I. Medina-Cabrera, Padma Kadiyala, Jiaqi Shi, Timothy L. Frankel, Eileen S. Carpenter, Michael D. Green, Cristina Mitrea, Costas A. Lyssiotis, and Marina Pasca di Magliano. Metabolic landscape of the healthy pancreas and pancreatic tumor microenvironment. JCI Insight, Aug 2024. URL: https://doi.org/10.1172/jci.insight.180114, doi:10.1172/jci.insight.180114. This article has 7 citations and is from a domain leading peer-reviewed journal.
(hashimoto2024plasticityandtumor pages 8-9): Ari Hashimoto and Shigeru Hashimoto. Plasticity and tumor microenvironment in pancreatic cancer: genetic, metabolic, and immune perspectives. Cancers, 16:4094, Dec 2024. URL: https://doi.org/10.3390/cancers16234094, doi:10.3390/cancers16234094. This article has 7 citations.
(hashimoto2024plasticityandtumor pages 9-10): Ari Hashimoto and Shigeru Hashimoto. Plasticity and tumor microenvironment in pancreatic cancer: genetic, metabolic, and immune perspectives. Cancers, 16:4094, Dec 2024. URL: https://doi.org/10.3390/cancers16234094, doi:10.3390/cancers16234094. This article has 7 citations.
(hashimoto2024plasticityandtumor pages 10-12): Ari Hashimoto and Shigeru Hashimoto. Plasticity and tumor microenvironment in pancreatic cancer: genetic, metabolic, and immune perspectives. Cancers, 16:4094, Dec 2024. URL: https://doi.org/10.3390/cancers16234094, doi:10.3390/cancers16234094. This article has 7 citations.
(gautam2023molecularandmetabolic pages 1-2): S. Gautam, S. Batra, and Maneesh Jain. Molecular and metabolic regulation of immunosuppression in metastatic pancreatic ductal adenocarcinoma. Molecular Cancer, Jul 2023. URL: https://doi.org/10.1186/s12943-023-01813-y, doi:10.1186/s12943-023-01813-y. This article has 76 citations and is from a highest quality peer-reviewed journal.
(vitorakis2024precisiontargetingstrategies pages 8-10): Nikolaos Vitorakis, Antonios N. Gargalionis, Kostas A. Papavassiliou, Christos Adamopoulos, and Athanasios G. Papavassiliou. Precision targeting strategies in pancreatic cancer: the role of tumor microenvironment. Cancers, 16:2876, Aug 2024. URL: https://doi.org/10.3390/cancers16162876, doi:10.3390/cancers16162876. This article has 17 citations.
(poyia2024theroleof pages 1-2): Fotini Poyia, Christiana M. Neophytou, Maria-Ioanna Christodoulou, and Panagiotis Papageorgis. The role of tumor microenvironment in pancreatic cancer immunotherapy: current status and future perspectives. International Journal of Molecular Sciences, 25:9555, Sep 2024. URL: https://doi.org/10.3390/ijms25179555, doi:10.3390/ijms25179555. This article has 24 citations.
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(do2024theroadahead pages 6-8): Chris T P Do, Jack Y Prochnau, Angel A. Dominguez, Pei Wang, and Manjeet Rao. The road ahead in pancreatic cancer: emerging trends and therapeutic prospects. Biomedicines, Sep 2024. URL: https://doi.org/10.3390/biomedicines12091979, doi:10.3390/biomedicines12091979. This article has 10 citations.
(saudeconde2024cancerassociatedfibroblastsin pages 1-2): Rita Saúde-Conde, Ayça Arçay Öztürk, Kosta Stosic, Oier Azurmendi Senar, Julie Navez, Christelle Bouchart, Tatjana Arsenijevic, Patrick Flamen, and Jean-Luc Van Laethem. Cancer-associated fibroblasts in pancreatic ductal adenocarcinoma or a metaphor for heterogeneity: from single-cell analysis to whole-body imaging. Biomedicines, 12:591, Mar 2024. URL: https://doi.org/10.3390/biomedicines12030591, doi:10.3390/biomedicines12030591. This article has 13 citations.
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(bonilla2024metaboliclandscapeof pages 25-29): Monica E. Bonilla, Megan D. Radyk, Matthew D. Perricone, Ahmed M. Elhossiny, Alexis C. Harold, Paola I. Medina-Cabrera, Padma Kadiyala, Jiaqi Shi, Timothy L. Frankel, Eileen S. Carpenter, Michael D. Green, Cristina Mitrea, Costas A. Lyssiotis, and Marina Pasca di Magliano. Metabolic landscape of the healthy pancreas and pancreatic tumor microenvironment. JCI Insight, Aug 2024. URL: https://doi.org/10.1172/jci.insight.180114, doi:10.1172/jci.insight.180114. This article has 7 citations and is from a domain leading peer-reviewed journal.
(bonilla2024metaboliclandscapeof pages 17-21): Monica E. Bonilla, Megan D. Radyk, Matthew D. Perricone, Ahmed M. Elhossiny, Alexis C. Harold, Paola I. Medina-Cabrera, Padma Kadiyala, Jiaqi Shi, Timothy L. Frankel, Eileen S. Carpenter, Michael D. Green, Cristina Mitrea, Costas A. Lyssiotis, and Marina Pasca di Magliano. Metabolic landscape of the healthy pancreas and pancreatic tumor microenvironment. JCI Insight, Aug 2024. URL: https://doi.org/10.1172/jci.insight.180114, doi:10.1172/jci.insight.180114. This article has 7 citations and is from a domain leading peer-reviewed journal.

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OpenScientist Report

Classifications

Mappings

Subtypes

Comorbidities

Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Environmental Factors

Biochemical Markers

Stages

Related Datasets

Clinical Trials

Computational Models

Source YAML

References & Deep Research

References

Deep Research

Disease Pathophysiology Research Template

Target Disease

Research Objectives

Required Information

1. Core Pathophysiology

2. Key Molecular Players

3. Biological Processes (for GO annotation)

4. Cellular Components

5. Disease Progression

6. Phenotypic Manifestations

Citation Requirements

Output Format

Comprehensive Research Report: Pathophysiology of Pancreatic Ductal Adenocarcinoma (PDAC)

Target disease and identifiers

1) Key concepts and definitions (current understanding)

1.1 Definition and core biological framing

1.2 Precursor lesions and progression model

2) Core pathophysiology (molecular and cellular mechanisms)

2.1 Cell-intrinsic oncogenic programs

KRAS-centered oncogenic signaling

Core tumor suppressor losses and malignant progression

2.2 Cell-extrinsic programs: the desmoplastic, immunosuppressive ecosystem

Desmoplasia and ECM barriers

CAF heterogeneity and immunoregulatory roles

Immunosuppressive leukocyte networks

2.3 Metabolic rewiring and immune–metabolic coupling

KRAS-driven glycolysis and hypoxia adaptation

Glutamine dependence and nutrient scavenging

Autophagy as immune evasion

3) Key molecular players, cell types, anatomical sites, and chemical entities

3.1 Genes/Proteins (HGNC; causality/implication)

3.2 Chemical entities (metabolites / ECM)

3.3 Cell types (CL-style)

3.4 Anatomical locations (UBERON-style)

4) Biological processes (GO-style) and cellular components (GO-CC-style)

4.1 Disrupted biological processes

4.2 Key cellular components

5) Disease progression: sequence of events (trigger → clinical manifestations)

5.1 Initiation: genetic + inflammatory “two-lens” model

5.2 Pre-invasive lesions → invasive carcinoma

5.3 Ecosystem maturation and therapy resistance

5.4 Metastasis and pre-metastatic niche conditioning

6) Phenotypic manifestations and clinical correlates

6.1 Survival and stage-at-diagnosis statistics (recent sources)

6.2 Mutation frequencies and clinical phenotypes

6.3 TME-driven phenotypes

7) Recent developments and latest research (prioritizing 2023–2024)

7.1 CAF subset refinement, senescence biology, and immunosuppression (2024)

7.2 Ecosystem quantification and CAF lineages (2024)

7.3 Metabolic ecosystem mapping and immune metabolism (2024)

7.4 Metastatic immunometabolic “hot spots” (2023)

8) Current applications and real-world implementations

8.1 Stromal/ECM targeting (hyaluronan and related strategies)

8.2 Immune targeting beyond PD-1/CTLA-4 (adenosine/CD73 axis)

8.3 Antigen/vaccine approaches including KRAS-directed vaccines (2024)

8.4 Imaging/biomarkers that operationalize stromal biology: 68Ga-FAPI PET

9) Expert opinions and analysis (authoritative sources)