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

ABSTRACT: Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with limited therapeutic options and poor outcomes due to metastasis. 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. Their exosomes, enriched in tumor-promoting growth factor receptors, suppress Caveolin 1 expression in tumor cells and induce an EMT-like phenotype that fuels aberrant HNSCC growth. In co-culture and in vivo, Gαq-silenced fibroblasts assemble into “railroad-track” structures that guide cancer cell migration and invasion. Reduced Gαq expression in human fibroblasts recapitulate these features underscoring a conserved mechanism of stromal activation. Overall, Gαq emerges as a key regulator of fibroblast plasticity and tumor-stroma interactions in HNSCC progression.

ORGANISM(S): Mus musculus

PROVIDER: GSE312614 | GEO | 2026/03/28

REPOSITORIES: GEO

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Project description:Vascular malformations are congenital lesions caused by somatic and germline mutations that disrupt developmental signaling pathways. Capillary malformations (CMs) typically present as port-wine stains in the skin and can also affect ocular and cerebral tissues in Sturge Weber Syndrome (SWS), leading to aesthetic, neurological, and ophthalmic complications. CMs are caused by a somatic mosaic mutation in the GNAQ gene in endothelial cells, leading to an activating p.R183Q substitution in the Gαq protein. The underlying mechanisms of Gαq-R183Q-driven CMs formation still remain unclear. To address this, we generated CRISPR/Cas9-engineered human dermal microvascular endothelial cells lacking endogenous Gαq, whilst expressing the Gαq-R183Q mutant instead. The Gαq-R183Q mutation strongly impaired endothelial cell migration and angiogenic sprouting capacity compared to wild-type controls. Next, using SILAC-based quantitative proteomics, we investigated the Gαq-R183Q-induced changes in the endothelial phosphoproteome. These analyses revealed prominent activation of calcineurin-NFAT signaling pathway in Gαq-R183Q-expressing endothelial cells, leading to dephosphorylation of NFAT1 and NFAT2 and the selective expression of their transcriptional target DSCR1.4. Immunofluorescence of patient-derived skin biopsies confirmed deregulation of NFAT1/2 and the expression of DSRC1 in endothelial cells, validating their potential importance in CMs. We further demonstrate that pharmacological inhibition of calcineurin with tacrolimus (FK506) could partially restore NFAT signaling, collective cell migration and sprouting in Gαq-R183Q endothelial cells. Intriguingly, the genetic depletion of the NFAT target DSCR1 in Gαq-R183Q cells fully rescued calcineurin/NFAT signaling as well as key endothelial functions. In summary, we uncovered a calcineurin-NFAT-DSCR1.4 signal transduction axis that is driven by Gαq-R183Q and established its importance for endothelial angiogenic properties. These findings highlight that calcineurin/NFAT signaling represents a promising therapeutic target to restore endothelial function in CMs.

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

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