Adipocyte-derived extracellular vesicles promote breast cancer cell malignancy through HIF-1α activity

Extracellular vesicles (EVs) are emerging key protagonists in intercellular communication between adipocytes and breast cancer (BC) cells. Here, we described a new mechanism by which EVs released by mature adipocytes promoted breast cancer cell malignancy "in vitro" and "in vivo". We found that adipocyte-derived EVs enhanced growth, motility and invasion, stem cell-like properties, as well as specific traits of epithelial-to-mesenchymal transition in both estrogen receptor positive and triple negative BC cells. Of note, adipocyte-derived EVs aid breast tumor cells in lung metastatic colonization after tail-vein injection in mice. These EV-mediated effects occur via the induction of HIF-1 alpha activity, since they were abrogated by the use of the HIF-1 alpha inhibitor KC7F2 or in cells silenced for HIF-1 alpha expression. Moreover, using an "ex vivo" model of obese adipocytes we found that the depletion of EVs counteracted the ability of obese adipocytes to sustain pro-invasive phenotype in BC cells. Interestingly, EVs released by undifferentiated adipocytes failed to induce aggressiveness and HIF-1 alpha expression. These findings shed new light on the role of adipocyte-derived EVs in breast cancer progression, suggesting the possibility to target HIF-1 alpha activity to block the harmful adipocyte-tumor cell dialogue, especially in obese settings.