Ral GTPases promote metastasis by controlling biogenesis and organotropism of exosomes

ABSTRACT: Cancer extracellular vesicles (EVs) mainly exert pro-tumoral functions by changing the phenotypes of stromal cells to the benefit of tumor growth and metastasis. In particular, they shuttle to distant organs and seed pre-metastatic niches facilitating subsequent colonization by circulating tumor cells. The levels of tumor secreted EVs have been correlated to tumor aggressiveness, however, the link between EV secretion mechanisms, their capacity to form pre-metastatic niches and the actual formation of metastasis remains obscure. Here, we show that two GTPases RalA and RalB control, through the phospholipase PLD1, the homeostasis of multi-vesicular bodies and thereby tune the biogenesis and secretion of a subtype of (pro-metastatic) EVs. Mice experiments revealed that RalA and RalB promote lung metastasis of mammary carcinoma cells without affecting their invasive behaviors. Importantly, we show in vivo that EVs from RalA or RalB depleted cells have limited organotropic capacities and, as a consequence, are less efficient in priming lung metastasis. Furthermore, we show that such EVs lack the adhesion molecule MCAM/CD146, which is responsible for EVs organotropism. Finally, we show that RalA and RalB have increased expression in human breast cancer patients with lung metastasis. Altogether, our study identifies Ral GTPases as central molecules linking the mechanisms of EVs secretion, cargo loading to their capacity to disseminate and induce pre-metastatic niches.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Lung

SUBMITTER: Francois Delalande  

LAB HEAD: Sarah CIANFERANI

PROVIDER: PXD020180 | Pride | 2021-09-09

REPOSITORIES: Pride