A TERRA–NONO Axis Drives Fibroblast Reprogramming in Cancer

Abstract

The molecular mechanisms linking chromosome homeostasis to fibroblast reprogramming into cancer-associated fibroblasts (CAFs) remain poorly understood. Here, we identify a clinically relevant, telomere-associated nuclear pathway that drives CAF activation across multiple human cancers. The long non-coding RNA TERRA is consistently elevated in CAFs from skin, lung, and breast tumors. We show that the androgen receptor (AR) normally represses TERRA transcription by binding subtelomeric regions. Loss of AR releases this repression, allowing TERRA to interact with the RNA-binding protein NONO, forming a CAF-specific nuclear complex that reprograms transcription toward a tumor-promoting state. Disrupting the TERRA-NONO complex, through TERRA silencing or pharmacologic NONO inhibition, reverses CAF activation and suppresses tumor-stroma interactions both in vitro and in vivo. Importantly, NONO inhibition restores normal fibroblast features in patient-derived actinic keratoses, cutaneous squamous cell carcinomas, and melanomas, underscoring the translational potential of this pathway and positioning the TERRA-NONO complex as a promising therapeutic target.