Role of extracellular vesicles in Renal Cell Carcinoma progression

• Grant number: 21/12951-6
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Effective date (Start): October 01, 2022
• Effective date (End): June 30, 2025
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Principal Investigator: Fausto Bruno dos Reis Almeida
• Grantee: Aline Seiko Carvalho Tahyra
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Cancer represents a set of malignant neoplastic diseases and is among the main causes of death in the world. Between the affected biological systems, kidney Cancer represents 4.6% of the total number of Cancer diagnoses in the world in 2020, according to the WHO. Despite the low percentage, this figure represents more than 430,000 cases, 90% of which correspond to the Renal Cell Carcinoma (RCC) type. This neoplasm originates in the tubular epithelial cells of the nephron, the functional unit of the kidney, and is associated, in addition to other risk factors, with advanced age and male gender. The 5-year relative survival is directly related to the stage of the tumor at the time of diagnosis, with a drastic drop in the rate when identified in the metastatic stage. Nowadays we are experiencing the "Golden Age" in relation to the state of the art in renal Cancer research, but to overcome the alarming epidemiological data, it is still necessary to deepen the understanding of the biology of this neoplasm. A new regulatory mechanism of tumor progression, which has gained prominence due to its relevance, corresponds to cell-cell communication via Extracellular Vesicles (EVs). Despite evidence of their contribution to tumorigenesis, metastasis and evasion of the immune system in several tumors, little is known about the role of EVs in the context of RCC. For this reason, this project aims to dyve into the contribution of the EVs to the regulation of mechanisms involved in the formation of the malignant RCC tumor such as hypoxia and angiogenesis, targeting the HIF-1 pathway and its downstream signaling. In addition, we aim to understand the participation of VEs in metastasis and evasion of the immune response mediated by PD-1/PD-L1 signaling, Fas-FasL and cytokines that modulate the response towards a protumorigenic profile. For these studies, the technique of three-dimensional culture on spheroids will be implemented, a technique that allows the mimicry of the tumor architecture with greater similarity than the two-dimensional culture. Thus, the development of this research project is expected to bring to light new perspectives on the contribution of EVs to the development of CCR, in order to open doors for new studies and technical applications such as the investigation of new biomarkers and therapeutic targets. (AU)