Loss of Gαq reshapes key fibroblast traits and drives matrix remodeling and aggressive progression of oral cancer tumors

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive cancer, with limited therapeutic options and a high mortality rate, primarily due to metastasis and recurrence. Tumor-stroma interactions, and namely cancer-associated fibroblasts (CAFs), are pivotal in shaping HNSCC progression. CAFs remodel the extracellular matrix (ECM) and secrete factors and vesicles that promote tumor growth and metastasis. The interplay between autophagy and endosomal/exosomal pathways has been suggested to regulate cellular secretory functions, but their potential involvement in HNSCC progression remains poorly understood. Since we have recently uncovered Gαq as a key modulator of autophagy, we have investigated the impact of Gαq loss on fibroblast functionality and on its crosstalk with oral HNSCC cells. We report that the absence of Gαq rewires murine embryonic fibroblasts towards CAF-like traits, leading to an increased pro-tumorigenic capacity of co-cultured human oral cancer cells through enhanced collagen I deposition and ECM remodeling. Strikingly, fibroblasts lacking Gαq display a shift in the balance of intracellular trafficking, degradative and secretory pathways. Exosomes released from Gαq-deficient fibroblasts show a marked enrichment in tumor-growth factor receptors and can facilitate aberrant tumor growth of HNSCC cells. Gαq-silenced fibroblasts promote the formation of "railroad-tracks" structures around HNSCC cells, enhancing their migratory and invasive capabilities both in vitro and in vivo, and reduced Gαq expression in human HNSCC CAFs correlates with enhanced tumor progression. Overall, our data put forward Gαq as a key regulator of the HNSCC tumor microenvironment by modulating fibroblast plasticity and functionality.