Sustaining Proliferative Signaling Module

Oncology Module sustaining_proliferative_signaling 22 disorders Pathograph 3

A conserved mechanism module for the first hallmark of cancer (Hanahan & Weinberg): the acquisition of growth-signal autonomy. Normal tissues tightly control the production and release of growth-promoting signals; cancer cells subvert this control to sustain chronic proliferation. The conserved causal chain runs from an oncogenic lesion that constitutively engages mitogenic signaling (activating receptor tyrosine kinase mutation/amplification, autocrine growth-factor loops, activating mutations in RAS/BRAF/PI3K, or loss of negative-feedback brakes such as PTEN/NF1) through constitutive RAS-MAPK and PI3K-AKT-mTOR signal output to growth-factor-independent cell-cycle entry and uncontrolled proliferation. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the tumor-type-specific driver (e.g., EGFR or ALK in NSCLC, BCR-ABL1 in CML, KIT/PDGFRA in GIST, activating BRAF V600E in melanoma) while preserving the conserved proliferative-signaling pattern. This is the proliferative counterpart to evading_growth_suppressors; together they capture the acquisition of autonomous proliferation plus loss of the antiproliferative brakes.

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Pathophysiology Nodes

3 shared nodes are defined in this module.

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Cell Types

No cell types are annotated for this module.

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Biological Processes

Cell Surface Receptor Tyrosine Kinase Signaling GO:0007169 INCREASED RAS Protein Signal Transduction GO:0007265 INCREASED ERK1 and ERK2 Cascade GO:0070371 INCREASED PI3K-AKT Signal Transduction GO:0043491 INCREASED Cell Population Proliferation GO:0008283 INCREASED

Notes

This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g., "sustaining_proliferative_signaling#Constitutive Mitogenic Pathway Activation"). The module defines the expected pathophysiology structure; conforming nodes in disorder files should include the corresponding cell types, biological processes, gene products, and causal edges, specialized to their tumor context. Key tumor-specific substitutions: NSCLC uses activating EGFR mutations or EML4-ALK fusion as the oncogenic driver; CML uses the BCR-ABL1 fusion kinase; GIST uses activating KIT/PDGFRA mutations; melanoma uses BRAF V600E. The complementary drug-mechanism view of RTK-proximal adaptor signaling is captured in rtk_grb2_signaling_adaptation. Key conformance target: "sustaining_proliferative_signaling#Constitutive Mitogenic Pathway Activation".

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Used By Disorder Entries

Acute Lymphoblastic Leukemia via Kinase-Activated B-ALL Signaling → Constitutive Mitogenic Pathway Activation

Adult Granulosa Cell Tumor of Ovary via FGFR1 Kinase-Domain Mutation in FOXL2-Wildtype Tumors → Oncogenic Growth-Signal Lesion

ALK-Rearranged Non-Small Cell Lung Cancer via ALK fusion oncoprotein formation → Oncogenic Growth-Signal Lesion , Constitutive ALK mitogenic and survival signaling → Constitutive Mitogenic Pathway Activation , ALK-dependent tumor-cell proliferation and survival → Growth-Factor-Independent Proliferation

Ameloblastoma via Somatic RTK-RAS-MAPK Driver Alterations → Oncogenic Growth-Signal Lesion , Oncogenic Odontogenic Epithelial Proliferation → Growth-Factor-Independent Proliferation

Anaplastic Thyroid Carcinoma via MAPK-Activating Truncal Driver Alteration → Oncogenic Growth-Signal Lesion

Chromophobe Renal Cell Carcinoma via mTORC1 Pathway Hyperactivation → Constitutive Mitogenic Pathway Activation

Chronic Myeloid Leukemia, BCR-ABL1 Positive via BCR-ABL1 Fusion Oncogene Formation → Oncogenic Growth-Signal Lesion , RAS-MAPK Pathway Hyperactivation → Constitutive Mitogenic Pathway Activation , Uncontrolled Myeloid Proliferation → Growth-Factor-Independent Proliferation

Ependymoma via Constitutive NF-kB Pathway Activation → Constitutive Mitogenic Pathway Activation , MYCN Amplification in Spinal Ependymoma → Oncogenic Growth-Signal Lesion

Epithelioid Hemangioendothelioma via CTGF-Integrin-RAS-MAPK Signaling → Constitutive Mitogenic Pathway Activation

ER-Positive Breast Cancer via PI3K-AKT-mTOR Pathway Activation → Constitutive Mitogenic Pathway Activation

Glioblastoma, IDH-Wildtype via EGFR/MET Pathway Activation → Constitutive Mitogenic Pathway Activation , PTEN Tumor Suppressor Loss → Oncogenic Growth-Signal Lesion

Glioma via EGFR Amplification and RTK-RAS-PI3K Mitogenic Signaling → Constitutive Mitogenic Pathway Activation

Glomus Tumor via Constitutive Mitogenic Pathway Activation

Hepatocellular Carcinoma via Enhanced Hepatocyte Proliferation → Growth-Factor-Independent Proliferation

Malignant Germ Cell Tumor of Ovary via KIT and RAS-PI3K Oncogenic Signaling Activation → Oncogenic Growth-Signal Lesion , Constitutive Mitogenic Pathway Activation , Growth-Factor-Independent Germ Cell Proliferation → Growth-Factor-Independent Proliferation

Mixed Phenotype Acute Leukemia via BCR-ABL1 Kinase-Driven Proliferative Signaling → Constitutive Mitogenic Pathway Activation

Neurofibromatosis Type 1 via RAS-MAPK Pathway Hyperactivation → Constitutive Mitogenic Pathway Activation

Non-Small Cell Lung Cancer via Oncogenic Driver Mutations → Oncogenic Growth-Signal Lesion

Ocular Melanoma via Gq/G11 Alpha Subunit Activating Mutation → Oncogenic Growth-Signal Lesion , PLC-beta/PKC/MAPK Cascade Activation → Constitutive Mitogenic Pathway Activation , Uveal Melanocyte Transformation and Intraocular Tumour Growth → Growth-Factor-Independent Proliferation

Pancreatic Ductal Adenocarcinoma via KRAS Oncogene Activation → Constitutive Mitogenic Pathway Activation

Splenic Marginal Zone Lymphoma via Constitutive NF-kB Pathway Activation → Constitutive Mitogenic Pathway Activation

Vulvar Carcinoma via PIK3CA-Activated HPV-Associated Signaling → Constitutive Mitogenic Pathway Activation , HRAS/RAS-MAPK Signaling Activation → Constitutive Mitogenic Pathway Activation , Clonal Squamous Cell Proliferation → Growth-Factor-Independent Proliferation

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Pathograph

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Pathophysiology

Oncogenic Growth-Signal Lesion

trigger

A genetic or epigenetic lesion confers growth-signal autonomy. Common routes include activating mutation or amplification of a receptor tyrosine kinase (EGFR, ERBB2/HER2, KIT, PDGFRA, MET, ALK, RET), establishment of autocrine growth-factor loops in which tumor cells produce ligands for their own receptors, constitutively activating mutations in downstream transducers (KRAS/NRAS/HRAS, BRAF, PIK3CA), or inactivation of negative-feedback regulators (PTEN, NF1, the SPRY/DUSP feedback machinery). Each route uncouples mitogenic signaling from the normal requirement for extrinsic growth-factor stimulation.

Cell Surface Receptor Tyrosine Kinase Signaling GO:0007169 INCREASED

Used by disorders

Adult Granulosa Cell Tumor of Ovary as FGFR1 Kinase-Domain Mutation in FOXL2-Wildtype Tumors

ALK-Rearranged Non-Small Cell Lung Cancer as ALK fusion oncoprotein formation

Ameloblastoma as Somatic RTK-RAS-MAPK Driver Alterations

Anaplastic Thyroid Carcinoma as MAPK-Activating Truncal Driver Alteration

Chronic Myeloid Leukemia, BCR-ABL1 Positive as BCR-ABL1 Fusion Oncogene Formation

Ependymoma as MYCN Amplification in Spinal Ependymoma

Glioblastoma, IDH-Wildtype as PTEN Tumor Suppressor Loss

Malignant Germ Cell Tumor of Ovary as KIT and RAS-PI3K Oncogenic Signaling Activation

Non-Small Cell Lung Cancer as Oncogenic Driver Mutations

Ocular Melanoma as Gq/G11 Alpha Subunit Activating Mutation

Downstream

Constitutive Mitogenic Pathway Activation The oncogenic lesion drives ligand-independent, constitutive activation of downstream proliferative signaling cascades.

Constitutive Mitogenic Pathway Activation

central effector

The oncogenic lesion produces chronic, ligand-independent flux through the core mitogenic cascades: the RAS-RAF-MEK-ERK (MAPK) pathway driving proliferative gene expression, and the PI3K-AKT-mTOR pathway driving growth, metabolism, and survival. This sustained signal output replaces the transient, tightly regulated pulses of signaling seen in normal growth-factor responses, and is the conserved central node that disorder-specific drivers converge upon.

RAS Protein Signal Transduction GO:0007265 INCREASED ERK1 and ERK2 Cascade GO:0070371 INCREASED PI3K-AKT Signal Transduction GO:0043491 INCREASED

Used by disorders

Acute Lymphoblastic Leukemia as Kinase-Activated B-ALL Signaling

ALK-Rearranged Non-Small Cell Lung Cancer as Constitutive ALK mitogenic and survival signaling

Chromophobe Renal Cell Carcinoma as mTORC1 Pathway Hyperactivation

Chronic Myeloid Leukemia, BCR-ABL1 Positive as RAS-MAPK Pathway Hyperactivation

Ependymoma as Constitutive NF-kB Pathway Activation

Epithelioid Hemangioendothelioma as CTGF-Integrin-RAS-MAPK Signaling

ER-Positive Breast Cancer as PI3K-AKT-mTOR Pathway Activation

Glioblastoma, IDH-Wildtype as EGFR/MET Pathway Activation

Glioma as EGFR Amplification and RTK-RAS-PI3K Mitogenic Signaling

Glomus Tumor

Malignant Germ Cell Tumor of Ovary

Mixed Phenotype Acute Leukemia as BCR-ABL1 Kinase-Driven Proliferative Signaling

Neurofibromatosis Type 1 as RAS-MAPK Pathway Hyperactivation

Ocular Melanoma as PLC-beta/PKC/MAPK Cascade Activation

Pancreatic Ductal Adenocarcinoma as KRAS Oncogene Activation

Splenic Marginal Zone Lymphoma as Constitutive NF-kB Pathway Activation

Vulvar Carcinoma as HRAS/RAS-MAPK Signaling Activation

Vulvar Carcinoma as PIK3CA-Activated HPV-Associated Signaling

Downstream

Growth-Factor-Independent Proliferation Constitutive mitogenic signaling drives cell-cycle entry independent of external growth-factor cues.

Growth-Factor-Independent Proliferation

consequence

Sustained mitogenic signaling drives the cell through the G1 restriction point and into repeated rounds of division without the normal requirement for extrinsic growth factors. The result is autonomous, chronic proliferation, the defining phenotype of this hallmark and a foundation for tumor growth.

Cell Population Proliferation GO:0008283 INCREASED

Used by disorders

ALK-Rearranged Non-Small Cell Lung Cancer as ALK-dependent tumor-cell proliferation and survival

Ameloblastoma as Oncogenic Odontogenic Epithelial Proliferation

Chronic Myeloid Leukemia, BCR-ABL1 Positive as Uncontrolled Myeloid Proliferation

Hepatocellular Carcinoma as Enhanced Hepatocyte Proliferation

Malignant Germ Cell Tumor of Ovary as Growth-Factor-Independent Germ Cell Proliferation

Ocular Melanoma as Uveal Melanocyte Transformation and Intraocular Tumour Growth

Vulvar Carcinoma as Clonal Squamous Cell Proliferation