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A key driver of tumor progression is the tumor microenvironment, particularly cancer-associated fibroblasts, which remodel the extracellular matrix and secrete pro-tumorigenic signals. Emerging evidence suggests that vesicle trafficking pathways regulate these secretory functions, though their role in HNSCC remains unclear. Building on our discovery of G\u03b1q as an autophagy regulator, we investigated how its absence reshapes fibroblast behavior and modulates crosstalk with HNSCC cells. We demonstrate that loss of G\u03b1q reprograms murine fibroblasts into a CAF-like phenotype through deregulated intracellular trafficking and increased ceramide accumulation. G\u03b1q-deficient fibroblasts show increased collagen I deposition, ECM remodeling, and secretion. Their exosomes, enriched in tumor-promoting growth factor receptors, suppress Caveolin-1 in tumor cells and induce an EMT-like phenotype that fuels HNSCC growth. In co-culture and in vivo, G\u03b1q-silenced fibroblasts form \u201crailroad-track\u201d structures guiding cancer cell migration and invasion. Reduced G\u03b1q expression in human fibroblasts recapitulates these features, identifying G\u03b1q as a key regulator of fibroblast plasticity and tumor\u2013stroma interactions in HNSCC progression.<\/jats:p>","DOI":"10.1038\/s44319-026-00751-2","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T16:06:55Z","timestamp":1775837215000},"page":"2639-2674","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Loss of G\u03b1q reshapes fibroblast traits and drives tumor-stroma remodeling in oral cancer progression"],"prefix":"10.1038","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9994-8069","authenticated-orcid":false,"given":"Inmaculada","family":"Navarro-L\u00e9rida","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7975-6481","authenticated-orcid":false,"given":"Raquel","family":"Huertas-L\u00e1rez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gemma","family":"Paredes-Garc\u00eda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dafne","family":"Garc\u00eda-Mateos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Isabel","family":"Jim\u00e9nez-L\u00f3pez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1630-890X","authenticated-orcid":false,"given":"Llara","family":"Prieto-Fern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5398-4962","authenticated-orcid":false,"given":"Ania","family":"Pascual","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8675-0037","authenticated-orcid":false,"given":"Virginia","family":"\u00c1vila-Oca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9097-6060","authenticated-orcid":false,"given":"Juan Antonio","family":"L\u00f3pez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9077-391X","authenticated-orcid":false,"given":"Miguel A","family":"del Pozo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6845-2789","authenticated-orcid":false,"given":"Sa\u00fal","family":"\u00c1lvarez-Teijeiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juana Mar\u00eda","family":"Garc\u00eda-Pedrero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ram\u00f3n","family":"Garc\u00eda-Escudero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1434-8449","authenticated-orcid":false,"suffix":"Jr","given":"Federico","family":"Mayor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7677-6882","authenticated-orcid":false,"given":"Catalina","family":"Ribas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,10]]},"reference":[{"key":"751_CR1","doi-asserted-by":"publisher","first-page":"e202006178","DOI":"10.1083\/jcb.202006178","volume":"219","author":"L Albacete-Albacete","year":"2020","unstructured":"Albacete-Albacete L, Navarro-L\u00e9rida I, L\u00f3pez JA, Mart\u00edn-Padura I, Astudillo AM, Ferrarini A, Van-Der-Heyden M, Balsinde J, Orend G, V\u00e1zquez J et al (2020) ECM deposition is driven by caveolin-1\u2013dependent regulation of exosomal biogenesis and cargo sorting. 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