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Modulation of mitochondrial dynamics as an approach for macrophage repolarization in cancer treatment

Grant number: 20/09535-8
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): February 01, 2021
Effective date (End): January 31, 2023
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal researcher:Pedro Manoel Mendes de Moraes Vieira
Grantee:Larissa Menezes dos Reis
Home Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Associated research grant:15/15626-8 - Macrophages and T lymphocytes immunometabolism in metabolic and inflammatory diseases, AP.JP

Abstract

Macrophages are heterogeneous and plastic populations of immune system cells that respond to environmental stimuli by modifying their functions within a wide spectrum of phenotypes, whereas M1 (inflammatory) and M2 (anti-inflammatory/repair) are the extreme subtypes of macrophages. A characteristic related to macrophages polarization is their metabolic adaptation, M1 type presents increased rates of glycolysis and lipid synthesis due to breaks in the tricarboxylic acid (TCA) cycle and by decreased rates of oxidative phosphorylation, which are associated with fragmented mitochondria (fission). On the other hand, M2 phenotype presents fully functional mitochondria, intact TCA cycle and increased rates of oxidative phosphorylation and oxidation fatty acid, which are associated with elongated mitochondria (fusion). Macrophages are an important component of the tumor microenvironment, which is formed by cancer cells secretome that recruits and modulates their components to benefit the tumorigenic process. In this context, M2 is the predominant phenotypic profile of macrophages, which contributes to angiogenesis, metastasis and resistance to treatments. In this project, our objective is to determine the role of mitochondrial dynamics for macrophages polarization on tumor context (in vitro e in vivo). For this purpose, we will use murine melanoma cell line B16F10 and macrophages isolated from mice with specific deletion of Mfn1/2 (prevents mitochondrial fusion) and Drp1 (prevents mitochondrial fission) in myeloid cells. After determining which pathways are involved in this process, we will test the polarization reprogramming using protein inhibitors (M2 to M1 phenotype) and will determine the effects that these reprogrammed macrophages will exercise on tumor progression in relation to proliferation, migration and invasion of cancer cells.

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