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

• Grant number: 17/26148-5
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: June 18, 2018
• End date: June 17, 2019
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Silvya Stuchi Maria-Engler
• Grantee: Érica Aparecida de Oliveira
• Supervisor: Colin Goding
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: University of Oxford, England
• Associated to the scholarship: 16/16554-3 - Emerging genes in melanoma progression and chemoresistance, BP.PD

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.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

DE OLIVEIRA, ERICA APARECIDA; CHAUHAN, JAGAT; DA SILVA, JULIA REZENDE; DA COSTA CARVALHO, LARISSA ANASTACIO; DIAS, DIOGO; DE CARVALHO, DANIELLE GONCALVES; MASAO WATANABE, LUIS ROBERTO; REBECCA, VITO W.; MILLS, GORDON; LU, YILING; et al. TOP1 modulation during melanoma progression and in adaptative resistance to BRAF and MEK inhibitors. PHARMACOLOGICAL RESEARCH, v. 173, NOV 2021. (16/16554-3, 18/20665-0, 17/04926-6, 18/14936-1, 17/26148-5)

SANDRI, SILVANA; WATANABE, LUIS R. M.; DE OLIVEIRA, ERICA APARECIDA; FAIAO-FLORES, FERNANDA; MIGLIORINI, SILENE; TIAGO, MANOELA; FELIPE-SILVA, ALOISIO; VAZQUEZ, VINICIUS DE LIMA; SOUZA, PAOLA DA COSTA; LOPES CONSOLARO, MARCIA EDILAINE; et al. Indoleamine 2,3-dioxygenase in melanoma progression and BRAF inhibitor resistance. PHARMACOLOGICAL RESEARCH, v. 159, SEP 2020. (17/04926-6, 17/26148-5, 12/05910-2, 11/19045-9, 16/16554-3, 13/05172-4, 15/10821-7)