Regulación metabólica de anoikis e implicaciones en la metástasis del melanoma

Circulating tumor cells are the key link between a primary tumor and distant metastases, but once in the bloodstream, loss of adhesion induces cell death known as anoikis. In order to identify the mechanisms relevant for melanoma circulating tumor cell survival, we performed RNA sequencing and discovered that detached melanoma cells and isolated melanoma circulating tumor cells rewire lipid metabolism by upregulating faay acid (FA) transport and FA beta- oxidation related genes. In melanoma patients, high expression of FA transporters and FA beta-oxidation enzymes significantly correlates with reduced progression-free and overall survival. Among the highest expressed regulators in melanoma circulating tumor cells were the carnitine transferases carnitine O-octanoyltransferase and carnitine acetyltransferase, which control the shuttle of peroxisome-derived medium chain FAs toward mitochondria to fuel mitochondrial FA beta-oxidation. Knock down of carnitine O-octanoyltransferase or carnitine acetyltransferase and short-term treatment with peroxisomal or mitochondrial FA beta-oxidation inhibitors thioridazine or ranolazine suppressed melanoma metastasis in mice. Carnitine O-octanoyltransferase and carnitine acetyltransferase depletion could be rescued by medium chain FA supplementation, indicating that the peroxisomal supply of FAs is crucial for the survival of non-adherent melanoma cells. Besides, using CRISPR-cas9 technology we identified the mitochondrial electron transport chain and cholesterol metabolism as possible mediators of anoikis resistance in melanoma. Our study highlights the great importance of metabolic rewiring in the metastatic process, identifying for the first time peroxisomal FA oxidation as a potential therapeutic target to challenge melanoma progression. Moreover, we propose to exploit the interaction between peroxisomes and mitochondria based on FA catabolism as a possible therapeutic opportunity thanks to the discovery of the antimetastatic activity of the drugs thiorizadine and ranolazine. These drugs have been approved by the Food and Drug Administration (FDA); therefore, our results have great translational potential.