Cancer-associated fibroblasts regulate DNA repair in pancreatic cancer through NDRG1-mediated R-loop processing
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.
Authors
- Rosa F. Hwang (ORCID: https://orcid.org/0000-0002-3103-6511)
- Christopher J. Halbrook (ORCID: https://orcid.org/0000-0002-3376-3114)
- Boryana Petrova (ORCID: https://orcid.org/0000-0001-9996-9353)
- David K. Chang (ORCID: https://orcid.org/0000-0002-4821-3078)
- Hanna M. Doh (ORCID: https://orcid.org/0000-0003-0781-611X)
- Petri Kursula (ORCID: https://orcid.org/0000-0001-8529-3751)
- Philip A. Cole (ORCID: https://orcid.org/0000-0001-6873-7824)
- Michael Oliphant
- Martin S. Taylor (ORCID: https://orcid.org/0000-0001-5824-142X)
- Simon F. Nørrelykke (ORCID: https://orcid.org/0000-0001-8302-526X)
- Zeljka Jutric (ORCID: https://orcid.org/0000-0003-1792-4376)
- Naama Kanarek (ORCID: https://orcid.org/0000-0002-2068-3908)
- Laura M. Selfors (ORCID: https://orcid.org/0000-0002-1317-7353)
- John G. Clohessy (ORCID: https://orcid.org/0000-0001-5186-9775)
- Taru E. Muranen (ORCID: https://orcid.org/0000-0003-4158-9002)
- Venla Mustonen (ORCID: https://orcid.org/0000-0002-5124-7711)
- Kayla A. Cruz (ORCID: https://orcid.org/0000-0001-8880-5804)
- Joseph E. Grossman (ORCID: https://orcid.org/0000-0002-2130-2783)
- Conor L. Evans (ORCID: https://orcid.org/0000-0003-2185-6505)
- Nina V. Kozlova (ORCID: https://orcid.org/0000-0002-4944-7917)
- Larysa Poluben (ORCID: https://orcid.org/0000-0002-5433-6963)
- R González
- L. Kerrie (ORCID: https://orcid.org/0000-0002-6504-160X)
- Salla Ruskamo (ORCID: https://orcid.org/0000-0002-9740-9077)
- Steve Wenglowsky
- RE Scully
- Josh Close
- Alica K. Beutel
- Su Min Hong (ORCID: https://orcid.org/0009-0006-8472-9924)
- Pradeep Mangalath
- Antoine A. Ruzette (ORCID: https://orcid.org/0009-0003-2203-0040)
- Rosie Upstill-Goddard
- Byanjana Thapa
- Monika Vyas
- Nicholas A. Willis
- Stephan Dreyer
Institutions
- Brigham and Women's Hospital (US)
- Boston Children's Hospital (US)
- Beth Israel Deaconess Medical Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- Harvard University (US)
- University of California, Irvine (US)
- Brown University (US)
- Beatson West of Scotland Cancer Centre (GB)
- Massachusetts General Hospital (US)
- University of California, Irvine Medical Center (US)
- Blueprint Medicines (United States) (US)
- Center for Systems Biology (US)
- University of Bergen (NO)
- University of Glasgow (GB)
- University of Oulu (FI)
Publication Details
- Journal
- Nature Cell Biology
- Published
- 2026-04-27
- DOI
- https://doi.org/10.1038/s41556-026-01938-4
- Primary Topic
- Mechanisms of cancer metastasis
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Science Foundation
- American Cancer Society
- Pew Charitable Trusts
- Prostate Cancer Foundation
- V Foundation for Cancer Research
- National Pancreas Foundation
- Harvard Medical School
- Boston Children's Hospital
- Royal Australasian College of Surgeons
- St. Vincent's Clinic Foundation
- Cancer Research UK
- Cancer Institute NSW
- Suomen Kulttuurirahasto
- National Institutes of Health
- National Health and Medical Research Council
- Cancer Council NSW