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Growing Desmoplastic Three-Dimensional Pancreatic Cancer Spheroids from Co-Culture
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ATM Deficiency Induces TGFβ-Mediated Stromal Programming in Pancreatic Cancer.

Elodie Roger1, Hannah M Mummey2, Eleni Zimmer1

  • 1Institute of Molecular Oncology and Stem Cell Biology, Ulm University Hospital, Ulm, Germany.

Cancer Research
|May 11, 2026
PubMed
Summary

ATM-deficient pancreatic cancer reprograms the tumor microenvironment, promoting aggressiveness and chemoresistance via TGF-β1 signaling. Targeting this pathway offers a promising precision oncology strategy.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) pathogenesis involves complex tumor microenvironment (TME) interactions.
  • The TME, characterized by bidirectional tumor-stroma communication, significantly influences cancer progression.

Purpose of the Study:

  • To investigate how ATM deficiency in tumor epithelium impacts the TME and cancer aggressiveness in PDAC.
  • To elucidate the molecular mechanisms underlying ATM-driven TME reprogramming and identify therapeutic targets.

Main Methods:

  • Genetically engineered mouse models and co-culture systems of pancreatic stellate cells (PSCs) and cancer-associated fibroblasts (CAFs).
  • Single-nucleus multiomics analysis of murine and human PDAC models.
  • Pharmacological inhibition of TGF-β signaling.

Main Results:

  • Tumoral ATM loss induced αSMA+ myofibroblastic (myCAF) differentiation in CAFs, irrespective of p53 status.
  • myCAFs promoted PDAC aggressiveness and chemoresistance.
  • ATM deficiency increased reactive oxygen species and contractility, leading to enhanced TGF-β1 secretion.

Conclusions:

  • ATM-deficient PDAC tumors reprogram the TME to promote cancer progression through TGF-β1 signaling.
  • Targeting TGF-β1 signaling can reverse myCAF differentiation and enhance chemosensitivity.
  • Dual targeting of intrinsic and extrinsic tumor vulnerabilities presents a potential precision oncology approach for ATM-null PDAC.