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Functional impact of the glutaminase enzyme interaction with pyruvate kinase M2 in the tumor microenvironment

Grant number: 21/13736-1
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): March 01, 2022
Effective date (End): February 28, 2027
Field of knowledge:Biological Sciences - Biochemistry - Chemistry of Macromolecules
Principal researcher:Sandra Martha Gomes Dias
Grantee:Bianca Novaes da Silva
Home Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovações (Brasil). Campinas , SP, Brazil

Abstract

Neoplastic cells share characteristics acquired during tumor development that are essential for Cancer progression. In particular, metabolism reprogramming is of paramount importance to meet the high energy and biosynthetic demand of these cells, in addition to being closely linked to epigenetic remodeling and aggressiveness gain. Recently, it has been discovered that Cancer cells live in a metabolic tug of war with immune system cells infiltrating the microenvironment with constant competition for nutrients and the production of metabolic wastes that lead to suppression of the immune attack and consequent tumor progression. There are breast tumor subtypes that depend on the high metabolization of glutamine by the glutaminase enzyme to survive, proliferate and gain aggressiveness; the enzyme Pyruvate Kinase M2 (PKM2), on the other hand, is a key modulating enzyme in deciding the glucose metabolism pathway. Post-translational modifications and levels of different metabolites make the enzyme transition between active and inactive states, leading to the production of pyruvate in the first case and the accumulation of intermediates such as ribose 5-phosphate and NADPH (important for the proliferative state), in the second case. Thus, the functioning of these two enzymes impacts on the level of different metabolites secreted by tumor cells and, therefore, on the phenotype of infiltrated lymphocytes and macrophages. We found in our laboratory that GLS and PKM2 interact directly in vitro and are co-immunoprecipitated from cells and that this interaction does not occur with the polymeric activated form of GLS, as well as decreasing the in vitro activity of PKM2. In this project, we intend, firstly, to deepen the understanding of the cellular compartment where this interaction takes place. We will also mimic (or eliminate) different post-translational modifications described for proteins (by site-directed mutagenesis), as well as evaluate the impact of metabolites and small molecules that modulate their activity (and oligomeric state) to look for a condition where the interaction is stabilized in the cells. This condition (and controls) will be evaluated by metabolomics to understand the impact of stabilization of the interaction of GLS and PKM2 in the cell metabolite pool. Finally, cells with these modifications will be implanted in syngeneic mice and characteristics such as tumor growth, metastasis and the profile of infiltrating immune cells will be determined. With this project we seek to understand how the cross-talk between two key tumor metabolic enzymes affects the metabolic fate of the nutrients glucose and glutamine and its importance in tumor development, discoveries which may lead to the development of new therapies. (AU)

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