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

• DOI: 10.7554/elife.61539
• Publication Date: 2021-01-06T13:02:34Z
• Authors: Shima Ghoroghi; Benjamin Mary; Annabel Larnicol; Nandini Asokan; Annick Klein; Naël Osmani; Ignacio Busnelli; François Delalande; Nicodème Paul; Sébastien Halary; Frédéric Gros; Laetitia Fouillen; Anne-Marie Haeberle; Cathy Royer; Coralie Spiegelha...; Gwennan André-Gré...; Vincent Mittelhei...; Alexandre Detappe; Kendelle Murphy; Paul Timpson; Raphaël Carapito; Marcel Blot-Chabaud; Julie Gavard; Christine Carapito; Nicolas Vitale; Olivier Lefebvre; Jacky G Goetz; Vincent Hyenne
• Keywords: 0301 basic medicine; 570; pre-metastatic niche; QH301-705.5; Science; 610; [SDV.CAN]Life Sciences [q-bio]/Cancer; Breast Neoplasms; Exosomes; GTP Phosphohydrolases; Mice; 03 medical and health sciences; cell biology; Human Umbilical Vein Endothelial Cells; exosome; Animals; Humans; human; Biology (General); Neoplasm Metastasis; mouse; Zebrafish; cancer biology; Cancer Biology; Q; R; Multivesicular Bodies; zebrafish; 3. Good health; Medicine; Ral GTPase

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.