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| Home > Publications database > ATM Deficiency Induces TGF-β-Mediated Stromal Programming in Pancreatic Cancer. |
| Home > Publications database > ATM Deficiency Induces TGF-β-Mediated Stromal Programming in Pancreatic Cancer. |
| Journal Article | DKFZ-2026-01130 |
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2026
AACR
Philadelphia, Pa.
Abstract: The tumor microenvironment (TME) actively contributes to pancreatic ductal adenocarcinoma (PDAC) pathogenesis through dynamic bidirectional tumor-stroma interactions. Here, 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 (PSC) and cancer-associated fibroblast (CAF) co-culture 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 TGF-β1 secretion. Pharmacological TGF-β 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 TGF-β signaling and identify dual targeting of intrinsic and extrinsic vulnerabilities as a promising precision oncology strategy.
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