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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| Variable | Model ID | Unit | Ontology Mappings | Phenotype Thresholds |
|---|---|---|---|---|
|
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 |
| Variable | Model ID | Unit | Ontology Mappings | Phenotype Thresholds |
|---|---|---|---|---|
|
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 |
name: Pancreatic Ductal Adenocarcinoma
creation_date: "2026-03-06T00:00:00Z"
updated_date: "2026-05-21T04:04:17Z"
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.
pathophysiology:
- name: KRAS Oncogene 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: DOI:10.3389/fmed.2024.1369136
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
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: 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
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.
- 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
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
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: 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
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
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
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: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
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
association: Somatic Gain-of-Function Mutation
inheritance:
- name: Somatic
evidence:
- reference: DOI:10.3389/fmed.2024.1369136
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
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
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
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: >-
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
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
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: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.
- name: Chronic Pancreatitis
description: >-
Long-standing chronic pancreatitis increases PDAC risk approximately 10-15 fold.
Chronic inflammation promotes ductal cell proliferation and accumulation of
oncogenic mutations.
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
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: MAXO:0000647
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: MAXO:0000647
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: 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
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 Ductal Adenocarcinoma
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.
classifications:
icdo_morphology:
classification_value: Adenocarcinoma
harrisons_chapter:
- classification_value: cancer
- classification_value: solid tumor
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.
Please provide a comprehensive research report on the pathophysiology of Pancreatic Ductal Adenocarcinoma. Focus on the molecular and cellular mechanisms underlying disease progression.
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
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).
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).
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).
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).
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).
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).
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).
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).
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).
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.
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
A 2024 review catalogs KRAS-directed vaccine efforts, including ELI-002 (NCT04853017) containing “G12D and G12R mutant KRAS peptides” (do2024theroadahead pages 6-8).
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.
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).
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).
| 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.
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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(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.
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(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.
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(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.
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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.