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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE272095 | GEO | 2026/04/27

REPOSITORIES: GEO

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Project description:Immunotherapeutics represent highly promising agents with the potential to improve patient outcomes in a variety of cancer types. Unfortunately, single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering from pancreatic ductal adenocarcinoma (PDAC). This may be due to the presence of a uniquely immunosuppressive tumor microenvironment (TME) present in PDACs, which creates a barrier to effective immune surveillance. Critical obstacles to immunotherapy in PDAC tumors include the dense desmoplastic stroma that acts as a barrier to T-cell infiltration and the high numbers of tumor-associated immunosuppressive cells. We have identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration. Single-agent FAK inhibition (VS-4718) dramatically limited tumor progression, resulting in a doubling of survival in the p48-Cre/LSL-KrasG12D/p53Flox/+ (KPC) mouse model of human PDAC. This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of tumor-infiltrating immature myeloid cells and immunosuppressive macrophages. We postulated that these desirable effects of FAK inhibition on the TME might render PDAC tumors more sensitive to immunotherapy. Accordingly, we found that VS-4718 rendered the previously unresponsive KPC mouse model responsive to anti-PD1 and anti-CTLA4 antagonists leading to a nearly tripling of survival times. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME thus rendering tumors more responsive to immunotherapy. We treated KP orthotopic tumor-bearing mice with vehicle and FAK inhibitor (FAKi) for 14 days, then extracted total RNA from tumor tissues.

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

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