Unraveling the role of HO-1 in modulating the tumor microenvironment

• Grant number: 23/02861-5
• Support Opportunities: Scholarships abroad - Research Internship - Scientific Initiation
• Start date: September 01, 2023
• End date: December 31, 2023
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Niels Olsen Saraiva Câmara
• Grantee: Lucas de Abreu Ferreira Machado
• Supervisor: Rodrigo Wagner Alves de Souza
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Harvard University, Boston, United States
• Associated to the scholarship: 21/09718-8 - Influence of the immune system on the induction of ferroptosis in tumor cells, BP.IC

Abstract

Heme-oxygenase 1 (HO-1) is an enzyme responsible for catalyzing the degradation of heme, generating products such as carbon monoxide (CO), biliverdin and ferrous iron (Fe²z). The expression of HO-1 is found in several types of cancer. The catabolites released by the breakdown of heme confer antioxidant, anti-inflammatory, anti-apoptotic and cytoprotective properties to HO-1 that can be used by tumor cells. The products released by the reaction catalyzed by HO-1 are capable of modulating the tumor microenvironment (TM) in order to make tumor cells more resistant to oxidative stress, apoptotic processes and chemotherapy treatments. Although HO-1 is presented as a pro-tumor factor, the high release of reactive iron resulting from the degradation of heme can generate a favorable metabolic context for the induction of ferroptosis, an iron-dependent regulated cell death process characterized by the accumulation of peroxidized lipids that generate rupture of the plasma membrane and cell death. Thus, we hypothesize that when heme groups are degraded by HO-1 in immune and tumor cells, it generates an increase in reactive iron levels that can trigger ferroptosis. Tumor-associated macrophages (TAM) presents an overexpression of HO-1 in TM. Studies have been shown that TAMs contribute to the supply of iron to tumor cells; however, the mechanisms that make this process possible need to be better explored. Due to its properties, it is reasonable to think that HO-1 may represent a possible mechanism by which TAMs acquire iron and, subsequently, deliver it to tumor cells. In that way, the objective of the project is to explore the expression of HO-1 in tumor cells and TAMs as a factor capable of increasing the sensitivity of tumor cells to ferroptosis due to the modulations of iron metabolism performed by this enzyme in the TM. In order to explore these mechanisms, in vitro and in vivo analyzes will be performed to verify the response generated both in tumor cells and in cells of the immune system. At the conclusion of this research project, we will have acquired important new insights into the role of heme in cell death by ferroptosis; 2) thoroughly tested in TAM the HO-1 contribution to increase the sensitivity to ferroptosis in tumor cells; and 3) lay the foundation for future development of heme-based therapeutics to decrease and avoid cancer progression. (AU)