Loss of Gαq reshapes fibroblast traits and drives tumor-stroma remodeling in oral cancer progression

A major driver of tumor progression is the tumor microenvironment, particularly cancer-associated fibroblasts (CAFs), which remodel the extracellular matrix and secrete pro-tumorigenic signals. Emerging evidence suggests that autophagy and vesicle trafficking pathways regulate these secretory functions, though their role in HNSCC remains unclear.

Building on our discovery of Gαq as a central autophagy regulator, we investigated how its absence reshapes fibroblast behavior and modulates crosstalk with oral HNSCC cells. Our findings demonstrate that loss of Gαq reprograms murine fibroblasts into a CAF-like phenotype, in part through deregulated intracellular trafficking and increased ceramide accumulation. Gαq-deficient fibroblasts display increased collagen I deposition, ECM remodeling, and a shift toward secretory activity.