A Druggable TGF-β-Mediated Stromal Programming Axis in ATM-Deficient Pancreatic Cancer

The tumor microenvironment (TME) actively contributes to pancreatic ductal adenocarcinoma (PDAC) pathogenesis via a dynamic bidirectional tumor–stroma dialog. Here, we show that homologous recombination-defective (HRD) neoplastic epithelium reprograms its TME in a genotype-specific manner to promote cancer aggressiveness. Autochthonous mouse models, co-culture systems, single-nucleus multiomics investigations and human PDAC specimens revealed that tumoral ATM serine/threonine kinase status impacts cancer-associated fibroblast fate towards αSMA+ myofibroblastic (myCAF) differentiation, independently of P53 loss-of-function. Vice versa, myCAFs foster cancer aggressiveness and specific chemoresistance patterns. Specifically, ATM deficiency is associated with the activation of reactive oxygen species and actomyosin signaling axis, increased contractility, and a greater TGF-β1 release. Pharmacological interference with TGF-β signaling reverts myofibroblast differentiation, chemoresistance, and tumor promotion in various ATM-deficient PDAC models. Overall, our findings demonstrate that both mouse and human HRD-PDACs reprogram their TME towards a cancer-promoting fate, making them suitable for combinatorial therapies targeting intrinsic vulnerabilities and extrinsic tumor–stroma crosstalks.