期刊
JOURNAL OF CELL BIOLOGY
卷 219, 期 11, 页码 -出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.202006178
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资金
- Ministerio de Ciencia, Innovacion y Universidades [CSD2009-0016, SAF2014-51876-R, SAF2017-83130-R, BFU2016-81912-REDC, IGP-SO-MINSEV1512-07-2016]
- Fundacio La Marato de TV3 [385/C/2019]
- Worldwide Cancer Research Foundation [AICR 15-0404]
- Fondo Europeo de Desarrollo Regional Una manera de hacer Europa
- European Union [641639]
- Actividades de I+D entre Grupos de Investigacion en Tecnologias, Comunidad Autonoma de Madrid/FEDER, Spain [S2018/NMT4443]
- Ministerio de Ciencia, Innovacion y Universidades grants [SAF201348201-R, SAF2016-80883-R]
- Institut National de la Sante et de la Recherche Medicale
- University of Strasbourg
- Ligue Contre le Cancer
- Institut National du Cancer
- Ministerio de Ciencia, Innovacion y Universidades predoctoral fellowship
- Severo Ochoa Excellence program [SVP-2013-06789]
- Asociacion Espanola Contra el Cancer [INVES191NAVA]
- Pro CNIC Foundation
- Severo Ochoa Center of Excellence [SEV-2015-0505]
The 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.
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