4.7 Article

ECM deposition is driven by caveolin-1-dependent regulation of exosomal biogenesis and cargo sorting

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

  1. Ministerio de Ciencia, Innovacion y Universidades [CSD2009-0016, SAF2014-51876-R, SAF2017-83130-R, BFU2016-81912-REDC, IGP-SO-MINSEV1512-07-2016]
  2. Fundacio La Marato de TV3 [385/C/2019]
  3. Worldwide Cancer Research Foundation [AICR 15-0404]
  4. Fondo Europeo de Desarrollo Regional Una manera de hacer Europa
  5. European Union [641639]
  6. Actividades de I+D entre Grupos de Investigacion en Tecnologias, Comunidad Autonoma de Madrid/FEDER, Spain [S2018/NMT4443]
  7. Ministerio de Ciencia, Innovacion y Universidades grants [SAF201348201-R, SAF2016-80883-R]
  8. Institut National de la Sante et de la Recherche Medicale
  9. University of Strasbourg
  10. Ligue Contre le Cancer
  11. Institut National du Cancer
  12. Ministerio de Ciencia, Innovacion y Universidades predoctoral fellowship
  13. Severo Ochoa Excellence program [SVP-2013-06789]
  14. Asociacion Espanola Contra el Cancer [INVES191NAVA]
  15. Pro CNIC Foundation
  16. Severo Ochoa Center of Excellence [SEV-2015-0505]

向作者/读者索取更多资源

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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