ATM Deficiency Induces TGFβ-Mediated Stromal Programming in Pancreatic Cancer
Menée à l'aide de modèles murins d'adénocarcinome canalaire du pancréas et d'organoïdes dérivés de tumeurs d'origine humaine, cette étude met en évidence un mécanisme par lequel une déficience de la kinase ATM dans les cellules cancéreuses favorise la modification du microenvironnement tumoral et la progression de la tumeur via l'augmentation de la sécrétion du facteur TGFbêta 1
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.
Cancer Research , article en libre accès, 2026