Oxidative metabolism in cultures of three-dimensional spheroids of melanoma resistant to BRAF inhibitor

Abstract

Melanoma is a complex disease with great aggressiveness and high mortality rates linked to metastatic capacity, immune system evasion and chemoresistance. The microenvironment and transcriptional plasticity, as well as the use of agents for targeted-directed therapy, contribute to the heterogeneity and selection of intrinsically resistant cells or a drug resistance phenotype. Heterogeneity is associated with cellular metabolic reprogramming, which is capable of sustaining proliferation in the process of transforming non-malignant cells into a neoplasic disease and it is an opportunity to be explored therapeutically for the treatment of melanoma. However, the development and progression of the tumor are influenced by the creation of a pro-tumor microenvironment and modeling of tumor complexity, in addition the monolayer models, often used, cannot reconstruct the complex and heterotypical in vitro cellular microenvironment. Thus, the organotypic culture, by promoting physiological parameters of organs and tumors and allowing to imitate the architecture of parental tissue, gained notoriety in studies on changes in the behavior of tumor cells. The present project aims to investigate tumor heterogeneity, with emphasis on oxidative metabolism, in a three-dimensional model of spheroids, and compare it with results previously obtained in 2D monoculture, which will enable progress understanding the evolution and possible ways to overcome melanoma resistance. (AU)