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

作者：N. V. Kozlova, Kayla Cruz, Antoine A. Ruzette, Hanna M. Doh, Nicholas A. Willis, Su Min Hong, R González, Monika Vyas, Laura M. Selfors, Stephan Dreyer, Rosie Upstill-Goddard, L. Kerrie, Steve Wenglowsky, Josh Close, Alica K. Beutel, Zeljka Jutric, Michael 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, RE Scully, Taru Muranen · 发表于：Nature Cell Biology · 年份：2026 · DOI：10.1038/s41556-026-01938-4 · 研究领域：Mechanisms of cancer metastasis、Chromatin Remodeling and Cancer、FOXO transcription factor regulation

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.