A novel DNA repair protein, N-Myc downstream regulated gene 1 (NDRG1), links stromal tumour microenvironment to chemoresistance

作者：Nina Kozlova, Kayla Cruz, Hanna M. Doh, Antoine A. Ruzette, Nicholas A. Willis, Su Min Hong, Raul S. González, Monika Vyas, Laura M. Selfors, Stephan B. Dreyer, Rosanna Upstill‐Goddard, Kerrie L Faia, Steve Wenglowsky, Joshua Close, Alica K. Beutel, Zeljka Jutric, Michael Oliphant, 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, Simon F. Nørrelykke, Ralph Scully, Taru Muranen · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2025 · DOI：10.1101/2025.01.22.634323 · 被引用次数：4 · 研究领域：Mechanisms of cancer metastasis、Chromatin Remodeling and Cancer、FOXO transcription factor regulation

Abstract In pancreatic ductal adenocarcinoma cancer (PDAC) drug resistance is a severe clinical problem and patients relapse within a few months after receiving the standard-of-care chemotherapy. One contributing factor to treatment resistance is the desmoplastic nature of PDAC; the tumours are surrounded by thick layers of stroma composing up to 90% of the tumour mass. This stroma, which is mostly comprised of extracellular matrix (ECM) proteins, is secreted by cancer-associated fibroblasts (CAFs) residing in the tumour microenvironment. However, the mechanistic basis by which the tumour stroma directly contributes to chemoresistance remains unclear. Here, we show that CAF-secreted ECM proteins induce chemoresistance by blunting chemotherapy-induced DNA damage. Mechanistically, we identify N-myc downstream regulated gene 1 (NDRG1) as a key protein required for stroma-induced chemoresistance that responds to signals from the ECM and adhesion receptors. We further show that NDRG1 is a novel DNA repair protein that physically interacts with replication forks, maintains DNA replication and functions to resolve stalled forks caused by chemotherapy. More specifically, NDRG1 reduces R-loops, RNA-DNA hybrids that are known to cause genomic instability. R-loops occur during replication-transcription conflicts in S-phase and after chemotherapy treatments, thus posing a major threat to normal replication fork homeostasis. We identify NDRG1 as highly expressed in PDAC tumours, and its h...