The role of TFEB/3 in response to nutrient limitation in MITF-positive and negative melanomas

Abstract

In cancer, intra-tumour phenotypic heterogeneity imposed by a dynamic microenvironment is increasingly recognized as a source of drug-resistance and a driver of metastatic spread. The in vivo microenvironment is highly complex and cancer cells will be exposed to a wide range of stresses including oxygen and nutrient limitation. The ability of cells to respond to the stresses encountered is key to their survival, and targeting their adaptive mechanisms is likely to have substantial therapeutic benefit. A key adaptive mechanism in response to nutrient limitation is the translocation into the nucleus of the transcription factors TFEB and TFE3 that increase, autophagy, lysosome biogenesis, and nutrient uptake while also slowing the cell cycle to reduce nutrient demand. Here we propose to examine the role of TFEB and TFE3 using a melanoma model where phenotype-switching driven by changes in expression of the TFEB/3 related factor MITF are well-characterized. Specifically we will identify the role of TFEB/3 in melanoma using 3D culture systems and 3D skin reconstructs, and determine their repertoire of target genes in response to different stimuli that induce their nuclear translocation. We predict that genes regulated by TFEB/TFE3 in response to glucose limitation will be different from those targeted in response to low glucose. The results will provide a key insight into the role in cancer of these key factors that we hypothesize to play a critical but unrecognized role in tumour progression.