Mitochondrial metabolism dictates the heterogeneity and resistance of melanoma

Abstract

Metastatic melanoma is the most aggressive among skin cancers, and current treatments based on the inhibition of BRAF / MEK become ineffective because the adaptive response favors the selection and proliferation of treatment-resistant tumor cells. It is well accepted that cancer cells undergo significant metabolic changes to be able to proliferate even in scarce nutrient environments, an example being the use of glutamine as an alternative source of carbon. These observations place mitochondria as a centralizing organelle of metabolism, since it is involved in metabolic changes and cellular signaling. In addition to ROS production by mitochondria, factors that control their own biogenesis may influence tumor proliferation. In this sense, the transcriptional cofactor PGC1±, necessary for mitochondrial biogenesis, can restore oxidative metabolism in melanoma. Expression of PGC1± is controlled by the MITF transcription factor and MAPK activation has been shown to alter mitochondrial oxidative metabolism via MITF / PGC1±. Thus, oxidative metabolism may be considered as an adaptive mechanism that limits the efficacy of BRAF inhibitors. In fact, it has been shown that vemurafenib chemotherapeutic resistant melanoma makes use of mitochondrial oxidative metabolism, characterized by elevated basal levels of mitochondrial respiration and ROS production. Analysis of the cell profile of melanoma patients revealed that the expression of genes reflected two phenotypes: one invasive and less proliferative and one less invasive and more proliferative. This inverse correlation found is not well understood, but has been shown to be related to MITF. The mechanism by which MITF is less expressed is unknown, but its low expression is related to resistance to BRAF / MEK inhibitors and an invasive profile. Thus, understanding the molecular mechanisms involved in decreasing MITF is critical to understanding the relationship between resistance to therapy and invasion. The present project aims to contribute to the knowledge of the functioning of energy metabolism in melanoma clonal subpopulations (stochastically isolated), with emphasis on the function of mitochondria in this process, exploring the profiles of subpopulations in relation to oxidative metabolism, expression of MITF and its regulation, as well as important proteins involved in these pathways. It is intended to understand how mitochondrial metabolism can dictate the heterogeneity and resistance of melanoma cells.