Journal
CELL REPORTS
Volume 5, Issue 5, Pages 1159-1168Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2013.10.050
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Funding
- NIH [R01 CA163592, R56 DK095811, R01 DK075555, AI060729, 2R32 MH018917-21]
- CTSA [UL1 RR024975, TR000445-06]
- NCI [P30 CA068485]
- VUMC CISR [CA68485, DK20593, DK58404, HD15052, DK59637, EY08126]
- American Cancer Society [RSG-09-170-01-CSM]
- American Heart Association [10PRE4030003]
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Unconventional secretion of exosome vesicles from multivesicular endosomes (MVEs) occurs across a broad set of systems and is reported to be upregulated in cancer, where it promotes aggressive behavior. However, regulatory control of exosome secretion is poorly understood. Using cancer cells, we identified specialized invasive actin structures called invadopodia as specific and critical docking and secretion sites for CD63- and Rab27a-positive MVEs. Thus, inhibition of invadopodia formation greatly reduced exosome secretion into conditioned media. Functionally, addition of purified exosomes or inhibition of exosome biogenesis or secretion greatly affected multiple invadopodia life cycle steps, including invadopodia formation, stabilization, and exocytosis of proteinases, indicating a key role for exosome cargoes in promoting invasive activity and providing in situ signaling feedback. Exosome secretion also controlled cellular invasion through three-dimensional matrix. These data identify a synergistic interaction between invadopodia biogenesis and exosome secretion and reveal a fundamental role for exosomes in promoting cancer cell invasiveness.
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