The role of necroptosis pathways in pathogenesis and progression of Gliomas

• Grant number: 20/10891-3
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: April 01, 2021
• End date: March 31, 2024
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Ricardo Weinlich
• Grantee: Ariane Barros Diniz
• Host Institution: Instituto Israelita de Ensino e Pesquisa Albert Einstein (IIEPAE). Sociedade Beneficente Israelita Brasileira Albert Einstein (SBIBAE). São Paulo , SP, Brazil

Abstract

A fundamental and common characteristic of all types of Cancer is the increased resistance to cell death, a characteristic that is closely related to the failure of clinical treatments and the lethality of this disease. More recently, the reduction or suppression of RIPK3 and/or MLKL expression, central molecules in the necroptosis pathway, a type of necrotic cell death, has been associated with worse prognosis in some types of Cancer, such as Lung, Bowel, Breast Cancer and Leukemias. Our research group demonstrated an inverse correlation in Gliomas, that is, the higher the expression of RIPK3 and/or MLKL, the worse the overall survival prognosis of these patients. Gliomas are primary tumors of glial cells, represent the most common type of Cancer in the Central Nervous System (CNS) and are classified into grades I to IV, according to their aggressiveness. This inverse correlation found specifically in Gliomas suggests that in these tumors, which are located in immunoprivileged sites, the necroptosis pathway facilitates tumor progression. However, despite the established correlation, there are so far no studies investigating the causal relationship between the expression of RIPK3 and MLKL and different outcomes in patients with Gliomas. Thus, this project aims to investigate whether and how the expression of RIPK3 and MLKL as well as the activation of the necroptosis pathway and Gliomas influences tumorigenesis and the progression of glial cell tumors. For that, we will establish murine models with orthotopic grafting of Gliomas with the same genetic background but expressing different levels of RIPK3 and MLKL. The main outcome parameters will be tumor growth and lethality. We will also analyze inflammatory and immunological parameters in the tumor tissue, since previous data from our group show that there are clear differences in these parameters in patients who express altered levels of RIPK3 and MLKL. At the end of the project, we hope to have contributed to understand whether altered levels of molecules of the necroptosis pathway in Gliomas have a causal relationship with their different outcomes and whether the inflammatory and/or immunological profiles found are involved in this pathogenesis mechanism. (AU)