Phenotype-specific melanoma uptake of fatty acid from human adipocytes activates AXL and CAV1-dependent beta-catenin nuclear accumulation
Chocarro-Calvo, A.; Jociles-Ortega, M.; Garcia-Martinez, J. M.; Louphrasitthiphol, P.; Vivas-Garcia, Y.; RAMIREZ-SANCHEZ, A.; Chauhan, J.; FIUZA, M. C.; DURAN, M.; GARCIA-JIMENEZ, C.; GODING, C.
Show abstract
Phenotypic diversity of cancer cells within tumors generated through bi-directional interactions with the tumor microenvironment has emerged as a major driver of disease progression and therapy resistance. Nutrient availability plays a critical role in determining phenotype, but whether specific nutrients elicit different responses on distinct phenotypes is poorly understood. Here we show, using melanoma as a model, that only MITFLow undifferentiated cells, but not MITFHigh cells, are competent to drive lipolysis in human adipocytes. In contrast to MITFHigh melanomas, adipocyte-derived free fatty acids are taken up by undifferentiated MITFLow cells via a fatty acid transporter (FATP)-independent mechanism. Importantly, oleic acid (OA), a monounsaturated long chain fatty acid abundant in adipose tissue and lymph, reprograms MITFLow undifferentiated melanoma cells to a highly invasive state by ligand-independent activation of AXL, a receptor tyrosine kinase associated with therapy resistance in a wide range of cancers. AXL activation by OA then drives SRC-dependent formation and nuclear translocation of a {beta}-catenin-CAV1 complex. The results highlight how a specific nutritional input drives phenotype-specific activation of a pro-metastasis program with implications for FATP-targeted therapies.
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