Ral GTPases promote breast cancer metastasis by controlling biogenesis and organ targeting of exosomes - Inserm - Institut national de la santé et de la recherche médicale Access content directly
Journal Articles eLife Year : 2021

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

Benjamin Mary
Nicodème Paul
Frédéric Gros
Vincent Mittelheisser

Abstract

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 vivo and 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.

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Cancer
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Dates and versions

inserm-03103515 , version 1 (08-01-2021)

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Shima Ghoroghi, Benjamin Mary, Annabel Larnicol, Nandini Asokan, Annick Klein, et al.. Ral GTPases promote breast cancer metastasis by controlling biogenesis and organ targeting of exosomes. eLife, 2021, 10, pp.e61539. ⟨10.7554/eLife.61539⟩. ⟨inserm-03103515⟩
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