Metabolism in the microenvironment and the role of metabolic exchanges in tumor progression

• Grant number: 21/05726-6
• Support Opportunities: Research Projects - Thematic Grants
• Duration: October 01, 2022 - September 30, 2027
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Sandra Martha Gomes Dias
• Grantee: Sandra Martha Gomes Dias
• Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovação (Brasil). Campinas , SP, Brazil
• Pesquisadores principais: Andre Luis Berteli Ambrosio
• Associated researchers: Adriana Franco Paes Leme ; Douglas Adamoski Meira ; Gabriela Maciel Vieira ; Guilherme Henrique Tamarindo ; Renata Spagolla Napoleão Tavares ; Tiago Góss dos Santos
• Associated scholarship(s): 22/13863-6 - Identification of new metabolic enzymes with filament capacity defined by transmission electron microscopy, BP.DR; 24/10896-6 - Glutaminase 2 and remodeling of the immune microenvironment in estrogen-positive breast cancer induced in transgenic mice by genome editing with CRISPR/Cas9, BP.PD; 24/05194-2 - Characterization of murine tumor cells for application as an experimental model in the study of the microenvironment in breast cancer., BP.TT; + associated scholarships 23/17617-2 - Analysis of the formation of aggregates of the metabolic enzymes GS and ALDH2 and their impact on mitochondrial function, BP.IC; 23/12636-9 - Development of CRISPR-Cas9 tools for the study of mitochondrial structure using expansion microscopy, BP.IC; 23/01388-4 - Identification of new enzymes capable of aggregating under conditions of nutrient deprivation and their role in tumor progression., BP.PD; 20/11992-8 - Study of the impact of glutaminase 2 on the immune microenvironment and the development of Estrogen-Positive Breast Cancer, BP.PD; 19/24563-0 - Evaluation of synergy between immune checkpoint blockade therapy with anti-PD-1 and glutaminase inhibition in the treatment of Triple-Negative Breast Cancer, BP.PD - associated scholarships

Abstract

To sustain the high proliferative rate, tumor cells have an increased demand for biosynthetic precursors used in the synthesis of macromolecules that will compose the daughter cells. For this, tumors consume a large amount of glucose and glutamine, mainly. The alteration in nutrient metabolism has been related to enzyme filamentation, a process conserved from yeast to mammalian cells, but still poorly understood from the point of view of tumor transformation. Furthermore, recent evidence suggests that dysregulation of tumor metabolism plays a crucial role in inhibiting the antitumor immune response and thus its progression and metastasis. It is known that in an immunosuppressive microenvironment, lymphocytes and macrophages operate with a metabolic disadvantage, since they are subjected to a shortage of crucial carbon sources (glucose and glutamine) and an increase in inhibitory signals. The subject of this proposal is the study of the molecular mechanisms behind the deregulation of nutrient metabolism and its role in the relationship of breast tumor cells with the immune system cells infiltrated in the microenvironment, and the tumor progression dependent on this interaction. Specifically, we stipulate two hypotheses, associated with which we have two objectives: hypothesis 1: GLS and GLS2, isoenzymes encoded by distinct genes, are related to the presence of distinct immune infiltrates in breast cancer; these profiles dictate different immune responses to the tumor. Objective 1: To study whether there is synergy between GLS inhibition (or its gene manipulation) and immunotherapy with anti-Programmed cell death protein 1 (PD-1) antibody on triple negative breast tumors (no hormone receptor expression) and confirm whether high expression/activity of GLS corresponds to the HOT-like (inflamed) immune profile predicted in silico; To study whether high expression/activity of GLS2 in ER+ tumors is related to COLD-type (immunosuppressed) tumors and whether GLS2 expression is related to resistance to hormone therapies. 2. HYPOTHESIS 2: GLS and other metabolic enzymes filament into cells, in a process driven by nutritional stress and under the control of tumor genetic lesions. Objective 2: To verify the impact of GLS filamentation on cellular mitophagy under glutamine deprivation and to search, in a group of 14 metabolic enzymes, for others that also filament under nutritional stress (glucose or glutamine); to verify the oncogenic signaling pathways that impact these phenomena and their importance in the tumor masses. Combining these two areas of activity, we will investigate the impact of GLS filamentation and other enzymes characterized by us on the profile of metabolites and immune cells infiltrated in tumor masses. Since the filament appears to obey nutritional stress processes and these phenomena affect the profile and activity of immune cells, we recommend that there may be a direct relationship between them. Thus, we will advance in two recent and innovative areas of research: 1. the study of enzymatic filamentation, with modern techniques of structural determination such as single particle Cryo-electron microscopy and Cryo-Focused ion bean electron tomography of cellular lamellae; 2. interface between glutamine metabolism in the tumor microenvironment and the phenotype and activity of infiltrated immune cells, a study that will benefit from the use of physiologically relevant tumor models such as patient tumors implanted in mice and tumor organoids. An in-depth understanding of metabolic challenges both at the molecular level and in the tumor microenvironment, and their impacts on the metabolic fitness of cancer cells and immune cells, may contribute to the discovery of new approaches combining metabolic fragilities and immunotherapy. (AU)

Publicações científicas

(Referências obtidas automaticamente do Web of Science e do SciELO, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores)

UNTERGASSER, ANDREAS; HELLEMANS, JAN; PFAFFL, MICHAEL W.; RUIJTER, JAN M.; VAN DEN HOFF, MAURICE J. B.; DRAGOMIR, MIHNEA P.; ADAMOSKI, DOUGLAS; DIAS, SANDRA MARTHA GOMES; REIS, RUI MANUEL; FERRACIN, MANUELA; et al. Disclosing quantitative RT-PCR raw data during manuscript submission: a call for action. MOLECULAR ONCOLOGY, v. 17, n. 5, p. 5-pg., 2023-03-27. (21/05726-6)