Role of the transcription factor HIF-1alpha in regulating the metabolism and function of tumor-associated macrophages

• Grant number: 24/11252-5
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: March 01, 2025
• End date: June 30, 2028
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Pedro Manoel Mendes de Moraes Vieira
• Grantee: João Nilton Barreto Andrade
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 20/16030-0 - Immunometabolic adaptation of tissue resident macrophages in health and disease, AP.TEM

Abstract

The tumor microenvironment (TME) is mainly composed of tumor cells, and mesenchymal and immune cells. Macrophages that reside within the tumor tissue are defined as tumor-associated macrophages (TAMs). TAMs can influence tumor growth and metastatic processes through interactions with other cell populations in the TME. Hypoxia is a common feature of the TME present in most solid tumors because of an imbalance between increased oxygen consumption and poor oxygen supply. As a result, there is the occurrence of rapid cell growth and vascularization problems. The broad cellular response triggered by hypoxia includes several factors, with the hypoxia-inducible factor HIF-1± being a key mediator of this process. Therefore, this project aims to analyze the role of the HIF-1± transcription factor in regulating the metabolism and function of TAMs. For this purpose, we will use three murine cancer lines (EO771, LL2/LLC1 and B16F10) and the NIH/3T3 line as a non-tumor control; and macrophages isolated from HIF-1±flox and VHLflox mice crossed with LysMcre and CSF1Rcre, targeting specifically for deletion in myeloid cells. After determining which pathways are involved in the observed phenotypes of both HIF-1± knockout and overexpressing macrophages in the TME, we will analyze the phenotype of TAMs. In addition, we will evaluate what effects TAMs can have on tumor progression in relation to the growth, proliferation and metastatic processes of cancer cells. With this, we hope to determine the mechanisms by which HIF-1± modulates TAMs.