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, multivesicular 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.

Automated summary

This study identifies Ral GTPases as central molecules linking the mechanisms of EV secretion and cargo loading to their capacity to disseminate and induce pre-metastatic niches. Depletion of RalA or RalB in cells leads to limited organotropic capacities in vivo and less efficient promotion of metastasis, as well as reduced levels of the adhesion molecule MCAM/CD146 in EVs, which favors EV-mediated metastasis by targeting to the lungs. RalA, RalB, and MCAM/CD146 are factors of poor prognosis in breast cancer patients.