Cancer-associated fibroblast-enriched TAGLN orchestrates HGF/c-MET-dependent transcriptional reprogramming in gastric cancer.

Abstract

Recurrence and peritoneal metastasis remain major challenges in gastric cancer (GC), highlighting the need to identify actionable stromal-tumor signaling circuits within the tumor microenvironment (TME). Integrated transcriptomic analyses and clinical validation identified TAGLN as a fibroblast-enriched factor associated with GC progression and poor prognosis. Functional studies showed that TAGLN expression in cancer-associated fibroblasts (CAFs) enhanced HGF production, at least in part through NF-κB activation, thereby promoting GC-cell malignant phenotypes via paracrine HGF/c-MET signaling. Mechanistically, HGF/c-MET activation promoted DDX5 phosphorylation, with Tyr595 identified as a critical phosphorylation site, and increased DDX5 nuclear accumulation. Nuclear DDX5 was enriched at the CAV1 promoter and enhanced CAV1 transcription, whereas CAV1 promoted malignant phenotypes by activating the PI3K/AKT/mTOR signaling. Salvianolic acid A (SA-A) showed TAGLN target engagement in DARTS and CETSA assays and attenuated TAGLN-associated CAF activity. In vivo, SA-A suppressed CAF-driven tumor growth and peritoneal dissemination. Collectively, these findings define a CAF-TAGLN/HGF/c-MET/DDX5/CAV1 signaling cascade linking stromal activation to tumor-cell transcriptional reprogramming and CAF-tumor crosstalk within the TME, and identify TAGLN as a potential therapeutic vulnerability for microenvironment-directed intervention in GC.