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

Area of Science:

• Oncology
• Molecular Biology
• Genomics

Background:

• Pancreatic ductal adenocarcinomas (PDACs) are aggressive, stroma-rich tumors known for treatment unresponsiveness and rapid relapse after chemotherapy.
• The tumor stroma, composed of extracellular matrix (ECM) proteins secreted by cancer-associated fibroblasts (CAFs), plays a critical role in PDAC progression.

Purpose of the Study:

• To investigate the link between CAF-secreted ECM proteins and DNA repair mechanisms in PDAC.
• To identify key mediators involved in sensing ECM signals and regulating DNA repair.

Main Methods:

• Utilized molecular biology techniques to identify key mediators.
• Investigated the role of NDRG1 in sensing ECM signals via adhesion receptors and SGK.
• Assessed NDRG1's association with replication forks and its function in DNA repair and R-loop resolution.
• Correlated NDRG1 expression levels with patient survival and chemotherapy response.

Main Results:

• Identified NDRG1 (N-myc downstream-regulated gene 1) as a crucial mediator linking ECM signals to DNA repair.
• Demonstrated that NDRG1 physically associates with replication forks, maintains replication, and resolves chemotherapy-induced stalled forks.
• Showed NDRG1's involvement in reducing R-loops, which are known to cause genomic instability.
• Found high NDRG1 expression in PDAC tumors, correlating with poor survival and chemotherapy response.

Conclusions:

• CAF-secreted ECM proteins unexpectedly enhance DNA repair through NDRG1.
• NDRG1 acts as a key sensor of ECM signals, promoting replication fork homeostasis.
• This study mechanistically links the tumor stroma to genomic instability regulation via NDRG1 and R-loop control in PDAC.