Adipocyte-Derived Extracellular Vesicles Endow Melanoma Cells with Stem-like Traits via PGC-1α-Mediated Mitochondrial Reprogramming.

Melanoma is an aggressive cancer characterized by a rapid metastatic process. Thus, understanding the mechanisms underlying its progression is urgently needed to improve patient outcomes. In this regard, there is consistent evidence of a tumor-sustaining crosstalk between melanoma and subcutaneous adipose tissue; however, the role of extracellular vesicles (EVs) in this communication still needs to be clarified. We demonstrated that the EVs derived from adipocytes did not alter melanoma cell proliferation but significantly promoted tumor cell migration and invasion by determining an enrichment in mesenchymal markers, such as N-cadherin and vimentin. In particular, these changes were accompanied by the transition towards a stem-like phenotype, characterized by enhanced spherogenic ability and ABCG2 upregulation; interestingly, this led to a reduced in vitro response to the BRAF inhibitor vemurafenib. Mechanistically, an increase in PGC-1α expression was found, resulting in higher mitochondrial mass and activity, ATP synthesis, and ROS overproduction; of note, treatment of melanoma cells with SR-18292 and XCT790, two inactivators of mitochondrial biogenesis, and N-acetylcysteine, a ROS scavenger, successfully counteracted the above EV-related effects, suggesting that mitochondrial function could be targeted to suppress the vesicular interactions between adipose tissue and melanoma. Taken together, these results highlight the crucial role played by EVs in melanoma stroma, pointing out the ability of adipocyte-derived vesicles to sustain cancer aggressiveness via PGC-1α-dependent mitochondrial reprogramming.