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<p>Pancreatic ductal adenocarcinomas (PDACs) are aggressive, stroma-rich tumours. They are unresponsive to treatments, and patients relapse quickly on DNA-damaging chemotherapies. PDAC stroma consists of extracellular matrix proteins (ECM), secreted by cancer-associated fibroblasts (CAFs). Here we show an unexpected link between CAF-secreted ECM proteins and enhanced DNA repair. We identify NDRG1 (N-myc downstream-regulated gene 1) as a key mediator that senses signals from the ECM via adhesion receptors and serum and glucocorticoid-activated kinase. We establish NDRG1 as a DNA repair factor that physically associates with replication forks, maintains DNA replication, resolves stalled forks caused by chemotherapies and is involved in reducing R-loops, RNA–DNA hybrids known to cause genomic instability. NDRG1 is highly expressed in PDAC tumours and its high expression correlates with poor disease-specific survival and poor response to chemotherapy. In conclusion, our data reveal an unexpected role for CAF-secreted ECM proteins in promoting DNA repair via NDRG1, mechanistically linking tumour stroma to replication fork homeostasis and R-loop regulation.</p>

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Cancer-associated fibroblasts regulate DNA repair in pancreatic cancer through NDRG1-mediated R-loop processing

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月27日

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  • Nina Kozlova,
  • Kayla A. Cruz,
  • Antoine A. Ruzette,
  • Hanna M. Doh,
  • Nicholas A. Willis,
  • Su Min Hong,
  • Raul S. Gonzalez,
  • Monika Vyas,
  • Laura M. Selfors,
  • Stephan Dreyer,
  • Rosie Upstill-Goddard,
  • Kerrie L. Faia,
  • Steve Wenglowsky,
  • Josh Close,
  • Alica Beutel,
  • Zeljka Jutric,
  • Michael U. J. Oliphant,
  • Larysa Poluben,
  • Byanjana Thapa,
  • Martin S. Taylor,
  • Venla Mustonen,
  • Pradeep Mangalath,
  • Christopher J. Halbrook,
  • Joseph E. Grossman,
  • Rosa F. Hwang,
  • John G. Clohessy,
  • Salla Ruskamo,
  • Petri Kursula,
  • Boryana Petrova,
  • Naama Kanarek,
  • Philip A. Cole,
  • David K. Chang,
  • Conor L. Evans,
  • Simon F. Nørrelykke,
  • Ralph Scully,
  • Taru Muranen

摘要

Pancreatic ductal adenocarcinomas (PDACs) are aggressive, stroma-rich tumours. They are unresponsive to treatments, and patients relapse quickly on DNA-damaging chemotherapies. PDAC stroma consists of extracellular matrix proteins (ECM), secreted by cancer-associated fibroblasts (CAFs). Here we show an unexpected link between CAF-secreted ECM proteins and enhanced DNA repair. We identify NDRG1 (N-myc downstream-regulated gene 1) as a key mediator that senses signals from the ECM via adhesion receptors and serum and glucocorticoid-activated kinase. We establish NDRG1 as a DNA repair factor that physically associates with replication forks, maintains DNA replication, resolves stalled forks caused by chemotherapies and is involved in reducing R-loops, RNA–DNA hybrids known to cause genomic instability. NDRG1 is highly expressed in PDAC tumours and its high expression correlates with poor disease-specific survival and poor response to chemotherapy. In conclusion, our data reveal an unexpected role for CAF-secreted ECM proteins in promoting DNA repair via NDRG1, mechanistically linking tumour stroma to replication fork homeostasis and R-loop regulation.