Albacete-Albacete, LucasNavarro-Lerida, InmaculadaLopez, Juan AntonioMartin-Padura, InesAstudillo, Alma MFerrarini, AlessiaVan-Der-Heyden, MichaelBalsinde, JesusOrend, GertraudVazquez, Jesusdel Pozo, Miguel Angel2021-06-292021-06-292020-11J Cell Biol. 2020; 219(11):e2020061781540-8140http://hdl.handle.net/20.500.12105/13210The composition and physical properties of the extracellular matrix (ECM) critically influence tumor progression, but the molecular mechanisms underlying ECM layering are poorly understood. Tumor-stroma interaction critically depends on cell communication mediated by exosomes, small vesicles generated within multivesicular bodies (MVBs). We show that caveolin-1 (Cav1) centrally regulates exosome biogenesis and exosomal protein cargo sorting through the control of cholesterol content at the endosomal compartment/MVBs. Quantitative proteomics profiling revealed that Cav1 is required for exosomal sorting of ECM protein cargo subsets, including Tenascin-C (TnC), and for fibroblast-derived exosomes to efficiently deposit ECM and promote tumor invasion. Cav1-driven exosomal ECM deposition not only promotes local stromal remodeling but also the generation of distant ECM-enriched stromal niches in vivo. Cav1 acts as a cholesterol rheostat in MVBs, determining sorting of ECM components into specific exosome pools and thus ECM deposition. This supports a model by which Cav1 is a central regulatory hub for tumor-stroma interactions through a novel exosome-dependent ECM deposition mechanism.engVoRhttp://creativecommons.org/licenses/by-nc-sa/4.0/AnimalsCaveolin 1ExosomesExtracellular MatrixFibroblastsMiceMice, KnockoutMultivesicular BodiesProteomeTenascinAtribución-NoComercial-CompartirIgual 4.0 Internacional3305316821911e20200617810.1083/jcb.202006178The Journal of cell biologyopen access