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

Fiche publication

Date publication

janvier 2021

Journal

eLife

Auteurs

Membres identifiés du Cancéropôle Est :
Dr GOETZ Jacky , Dr LEFEBVRE Olivier , Mme ROYER Cathy , Dr CARAPITO Christine , Dr CARAPITO Raphaël , Dr GROS Frédéric , Dr VITALE Nicolas , Dr DETAPPE Alexandre , Dr HYENNE Vincent , Dr OSMANI Naël

Tous les auteurs :
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 AM, Royer C, Spiegelhalter C, André-Grégoire G, Mittelheisser V, Detappe A, Murphy K, Timpson P, Carapito R, Blot-Chabaud M, Gavard J, Carapito C, Vitale N, Lefebvre O, Goetz JG, Hyenne V

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/33404012

Résumé

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 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.