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| Home > In process > ATM Deficiency Induces TGFβ-Mediated Stromal Programming in Pancreatic Cancer. |
| Home > In process > ATM Deficiency Induces TGFβ-Mediated Stromal Programming in Pancreatic Cancer. |
| Journal Article | DZNE-2026-00766 |
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2026
AACR
Philadelphia, Pa.
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Please use a persistent id in citations: doi:10.1158/0008-5472.CAN-26-0138
Abstract: The tumor microenvironment (TME) actively contributes to pancreatic ductal adenocarcinoma (PDAC) pathogenesis through dynamic bidirectional tumor-stroma interactions. In this study, we demonstrated that ATM-deficient tumor epithelium reprograms the TME in a genotype-specific manner to enhance cancer aggressiveness. In genetically engineered mouse models, pancreatic stellate cell and cancer-associated fibroblast (CAF) coculture systems, single-nucleus multiomics, and human PDAC models, tumoral loss of ATM serine/threonine kinase drove CAFs toward αSMA+ myofibroblastic (myCAF) differentiation, independently of p53 status. The myCAFs, in turn, promoted cancer aggressiveness and chemoresistance. Mechanistically, ATM deficiency increased reactive oxygen species and contractility signaling, enhancing TGFβ1 secretion. Pharmacologic TGFβ inhibition reversed myCAF differentiation, sensitized tumors to chemotherapy, and impaired tumor progression in both murine and human ATM-null models. These findings reveal that ATM-deficient tumors shape a cancer-promoting niche via TGFβ signaling and identify dual targeting of intrinsic and extrinsic vulnerabilities as a promising precision oncology strategy.TGF-β-driven myofibroblastic stromal differentiation in ATM-deficient pancreatic cancer generates a genotype-specific tumor microenvironment, providing a targetable axis and highlighting the need to integrate epithelial genotype and stromal context in pancreatic cancer therapy.
Keyword(s): Animals (MeSH) ; Ataxia Telangiectasia Mutated Proteins: deficiency (MeSH) ; Ataxia Telangiectasia Mutated Proteins: genetics (MeSH) ; Humans (MeSH) ; Pancreatic Neoplasms: pathology (MeSH) ; Pancreatic Neoplasms: genetics (MeSH) ; Pancreatic Neoplasms: metabolism (MeSH) ; Mice (MeSH) ; Transforming Growth Factor beta: metabolism (MeSH) ; Tumor Microenvironment (MeSH) ; Carcinoma, Pancreatic Ductal: pathology (MeSH) ; Carcinoma, Pancreatic Ductal: genetics (MeSH) ; Carcinoma, Pancreatic Ductal: metabolism (MeSH) ; Signal Transduction (MeSH) ; Cancer-Associated Fibroblasts: metabolism (MeSH) ; Cancer-Associated Fibroblasts: pathology (MeSH) ; Stromal Cells: metabolism (MeSH) ; Stromal Cells: pathology (MeSH) ; Cell Differentiation (MeSH) ; Cell Line, Tumor (MeSH) ; Pancreatic Stellate Cells: metabolism (MeSH) ; Pancreatic Stellate Cells: pathology (MeSH) ; Disease Models, Animal (MeSH) ; Myofibroblasts: metabolism (MeSH) ; Myofibroblasts: pathology (MeSH) ; Ataxia Telangiectasia Mutated Proteins ; Transforming Growth Factor beta ; ATM protein, human ; Atm protein, mouse
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