Scholarship 24/10896-6 - Neoplasias, Neoplasias mamárias - BV FAPESP
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Glutaminase 2 and remodeling of the immune microenvironment in estrogen-positive breast cancer induced in transgenic mice by genome editing with CRISPR/Cas9

Grant number: 24/10896-6
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Start date until: August 01, 2024
End date until: July 31, 2026
Field of knowledge:Biological Sciences - Biochemistry - Chemistry of Macromolecules
Principal Investigator:Sandra Martha Gomes Dias
Grantee:Pedro Paranhos Tanaka
Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovação (Brasil). Campinas , SP, Brazil
Associated research grant:21/05726-6 - Metabolism in the microenvironment and the role of metabolic exchanges in tumor progression, AP.TEM

Abstract

The relationship between tumor cells and their microenvironment governs essential aspects of tumor biology, including the success of therapeutic responses and clinical prognosis. Immune cells, whether myeloid or lymphoid, interact with tumor cells but their actions can be inhibited by potent immunosuppressive mechanisms. The performance of immune functions is also affected by tumor metabolism itself, as, within the tumor microenvironment, carbon sources are rapidly exploited by cancer cells and are scarcely available for the immune machinery. In addition to consuming carbon, cancer cells secrete metabolic wastes that have immunosuppressive effects. Previously, our group demonstrated that high expression of the glutaminase enzyme GLS2, responsible for glutamine metabolism, is associated with a worse prognosis and lower survival in breast cancer patients, particularly in luminal and estrogen receptor-positive (ER+) subtypes (the majority of breast tumors). Such tumors with elevated GLS2 expression are not only associated with resistance to hormone therapy but are also related to suppression of the Th1 response and greater polarization of alternatively activated macrophages (i.e., with a pro-tumoral profile). Therefore, this project aims to investigate how GLS2 is contextualized in ER+ breast cancer and its immune microenvironment. For this purpose, we will develop in vivo assays, where ER+ breast tumors will be induced in LSL-Cas9 mice with the integration of adenoviral vectors that condition gene-specific knockouts/mutations, including the GLS2 enzyme. The developed tumors will be evaluated by immunohistochemistry, flow cytometry (to assess immune infiltrates), metabolomics (to analyze glutamine metabolism), and single-cell RNA-seq for gene, population, and signaling profiling. This work is relevant because it is innovative in the fields of tumor metabolism and the analysis of the tumor-immune microenvironment relationship in response to a metabolic insult. We believe this study will highlight new therapeutic pathways for ER+ breast cancer, especially for tumors refractory to hormone therapy.

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