120 | Exploring CD36-dependent lipid uptake in melanoma–adipocyte communication mediated by extracellular vesicles

Gaia Giannitti¹, Kinga Kamińska^2|3, Sara Marchesi¹, Riccardo Garavaglia¹, Ivan Preosto¹, Małgorzata Grzesiak², Fabrizio Fontana¹ | ¹Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", University of Milan, Italy; ²Department of Endocrinology, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, Krakow, Poland; ³Department of Animal Biotechnology, University of Agriculture in Krakow, Poland.

Melanoma is a highly aggressive cancer characterized by a strong metastatic potential, highlighting the importance of deciphering the mechanisms underlying its progression to improve clinical outcomes. Emerging evidence indicates a tumor-promoting interaction between melanoma cells and subcutaneous adipose tissue; however, the role of extracellular vesicles (EVs) in mediating this crosstalk remains poorly defined. Here, we show that melanoma-derived EVs reprogram adipocytes toward a cancer-associated state by activating the cAMP/PKA/HSL signaling pathway, thereby enhancing lipolysis and inducing the release of free fatty acids (FFAs). These FFAs are subsequently taken up by melanoma cells, where they fuel tumor growth by promoting proliferation, clonogenic capacity, survival, migration, invasion, and resistance to anoikis. We further identify the fatty acid transporter CD36 as a critical mediator of this metabolic interaction, as its pharmacological inhibition using sulfo-N-succinimidyl oleate or SMS21 effectively abolishes the pro-tumorigenic effects of adipocyte-derived FFAs. Overall, our data support a model in which melanoma-derived EVs drive a metabolic feedback loop with adipocytes that enhances tumor aggressiveness, and they identify CD36 as a potential therapeutic target to disrupt this pathogenic communication.