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Ral GTPases promote breast cancer metastasis by controlling biogenesis and organ targeting of exosomes


Cancer extracellular vesicles (EVs) shuttle at distance and fertilize pre-metastatic niches facilitating subsequent seeding by tumor cells. However, the link between EV secretion mechanisms and their capacity to form pre-metastatic niches remains obscure. Using mouse models, we show that GTPases of the Ral family control, through the phospholipase D1, multi-vesicular bodies homeostasis and tune the biogenesis and secretion of pro-metastatic EVs. Importantly, EVs from RalA or RalB depleted cells have limited organotropic capacities in vivoand are less efficient in promoting metastasis. RalA and RalB reduce the EV levels of the adhesion molecule MCAM/CD146, which favors EV-mediated metastasis by allowing EVs targeting to the lungs. Finally, RalA, RalB, and MCAM/CD146, are factors of poor prognosis in breast cancer patients. Altogether, our study identifies RalGTPases as central molecules linking the mechanisms of EVs secretion and cargo loading to their capacity to disseminate and induce pre-metastatic niches in a CD146-dependent manner.

Type Journal
ISBN 2050-084X (Electronic) 2050-084X (Linking)
Authors Ghoroghi, S.; Mary, B.; Larnicol, A.; Asokan, N.; Klein, A.; Osmani, N.; Busnelli, I.; Delalande, F.; Paul, N.; Halary, S.; Gros, F.; Fouillen, L.; Haeberle, A. M.; Royer, C.; Spiegelhalter, C.; Andre-Gregoire, G.; Mittelheisser, V.; Detappe, A.; Murphy, K.; Timpson, P.; Carapito, R.; Blot-Chabaud, M.; Gavard, J.; Carapito, C.; Vitale, N.; Lefebvre, O.; Goetz, J. G.; Hyenne, V.
Responsible Garvan Author Prof Paul Timpson
Publisher Name eLife
Published Date 2021-01-31
Published Volume 10
Published Pages e61539
Status Published in-print
DOI 10.7554/eLife.61539
URL link to publisher's version
OpenAccess link to author's accepted manuscript version