Élodie Roger, Hannah M Mummey, Eleni Zimmer, Dharini Srinivasan, Anna Härle, Loïc Moubri, Alica K. Michels, Rima Singh, Menar Ekizce, Michael K. Melzer, Yun Lee, Austin Silva, Luisa Härle, Thomas Engleitner, Frank Arnold, Mareen Morawe, Benjamin Karem. Naggay, Juliane Schneider, Leonard Gilberg, Julia P. Mosler, Christina Ludwig, Chen Meng, Maximilian Hirschenberger, Victoria Hunszinger, Klaus Kluck, Martina Kirchner, Anna-Lena Volckmar, Mareike Wirth, Mohamed S. S. Alhamdani, Jörg D. Hoheisel, J.-Matthias Löhr, Thomas Seufferlein, Alireza Abaei, Ralf Kemkemer, Roland Rad, Jan Budczies, Medhanie A. Mulaw, Patrick C. Hermann, Mark M. Haenle, Konstantin M. J. Sparrer, Christopher J. Halbrook, Kyle J. Gaulton, Konrad Steinestel, Albrecht Stenzinger, Nelson Dusetti, Lukas Perkhofer, Johann Gout, A Kleger
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. SIGNIFICANCE: 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.