ATM Deficiency Induces TGF-β-Mediated Stromal Programming in Pancreatic Cancer

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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Journal
Cancer Research
Published
2026-05-11
DOI
https://doi.org/10.1158/0008-5472.can-26-0138
Primary Topic
Pancreatic and Hepatic Oncology Research
Type
article
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article

ATM Deficiency Induces TGF-β-Mediated Stromal Programming in Pancreatic Cancer

Juliane Schneider, Alireza Abaei, Élodie Roger, Leonard Gilberg et al.
Cancer Research
Pancreatic and Hepatic Oncology Research
article

ATM Deficiency Induces TGF-β-Mediated Stromal Programming in Pancreatic Cancer

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

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.

Cancer Research
Memorial Sloan Kettering Cancer Center (US), University of San Diego (US), Munich University of Applied Sciences (DE), German Cancer Research Center (DE), Universität Ulm (DE), University of California, Irvine (US), Heidelberg University (DE), German Center for Neurodegenerative Diseases (DE), University Hospital Heidelberg (DE), Karolinska Institutet (SE), Frauenklinik der Technischen Universität München (DE), Bundeswehrkrankenhaus (DE), Irvine University (US), Centre de Recherche en Cancérologie de Marseille (FR), Leibniz-Institute for Food Systems Biology at the Technical University of Munich (DE), Institut Paoli-Calmettes (FR), University Hospital Ulm (DE), Bundeswehrkrankenhaus Ulm (DE), Technische Hochschule Ulm (DE), Reutlingen University (DE), Technical University of Munich (DE)
Openalex Percentile: Top 7%
Pancreatic and Hepatic Oncology Research
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