Examination of Mitochondrial DNA Instability in Melanoma Tumorigenesis and Metastasis

• Grant number: 15/21940-7
• Support type: Scholarships abroad - Research Internship - Doctorate
• Effective date (Start): March 01, 2016
• Effective date (End): November 30, 2016
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Wilson Araújo da Silva Junior
• Grantee: Luíza Ferreira de Araújo
• Supervisor abroad: Andrew Phillip West
• Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Local de pesquisa : Southern Methodist University (SMU), United States
• Associated to the scholarship: 13/25119-0 - Energetic metabolism study on melanoma progression based on mitochondrial genome instability, BP.DR

Abstract

Melanoma is a malignancy caused by accumulation of genetic alterations in melanocytes, and it is the deadliest form of skin cancer due to its high metastatic potential. The genetic basis of melanoma is well characterized, and activating mutations in the RAF/RAS pathway (i.e. BRAFV600E) combined with other genetic mutations, i.e. PTEN silencing, have been shown to induce metastatic melanoma. Moreover, mounting evidence suggests that mutations in proto-oncogenes and tumor suppressors play an important role in altering cancer cell metabolism and mitochondrial function. This reprogramming consists in a metabolic shift in the cancer cells from OXPHOS to aerobic glycolysis, also known as the Warburg effect, resulting in increased and lactate production mitochondrial stress signaling. In addition, several groups have reported that mitochondrial dysfunction in tumor fibroblasts and stromal cells can feed back and further enhance tumor growth and invasiveness, a phenomenon termed the 'Reverse Warburg effect'. Dysfunctional mitochondria play a central role in both models, although much remains unclear. Previous studies from the sponsor's lab have shown that animal models exhibiting mitochondrial stress display enhanced melanoma growth. In this proposal, we intend to explore how mitochondrial DNA stress triggers metabolic and signaling alterations to alter melanoma growth using a BRAFV600E /PTENnull inducible murine melanoma model. The findings from this research will contribute to our understanding of how mitochondria influence cancer progression and may have important implications for treating melanoma and other malignancies.

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)

ARAUJO, L. F.; SIENA, A. D. D.; PLACA, J. R.; BROTTO, D. B.; BARROS, I. I.; MUYS, B. R.; BIAGI JR, C. A. O.; PERONNI, K. C.; SOUSA, J. F.; MOLFETTA, G. A.; WEST, L. C.; WEST, A. P.; LEOPOLDINO, A. M.; ESPREAFICO, E. M.; SILVA JR, W. A. Mitochondrial transcription factor A (TFAM) shapes metabolic and invasion gene signatures in melanoma. SCIENTIFIC REPORTS, v. 8, SEP 21 2018. Web of Science Citations: 3.