Characterization of the relationship between NRF2 and the mTOR/S6Ks pathway using genetically engineered mouse models (GEMMs)

• Grant number: 22/10223-6
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: January 08, 2023
• End date: December 31, 2023
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Fernando Moreira Simabuco
• Grantee: Mariana Camargo Silva Mancini
• Supervisor: Thales Papagiannakopoulos
• Host Institution: Faculdade de Ciências Aplicadas (FCA). Universidade Estadual de Campinas (UNICAMP). Limeira , SP, Brazil
• Institution abroad: NYU Langone Medical Center, United States
• Associated to the scholarship: 19/25582-9 - Study of the role of Nrf2 protein in metabolism regulation and redox control in response to natural food-derived compounds in Prostate Cancer cells, BP.DD

Abstract

mTOR pathway has been suggested as a central mechanism that converges different signaling pathways to coordinate cell growth and is commonly reported overactivated in cancer. Once activated by growth factors, amino acids, or energy (ATP/AMP ratio), mTOR induces the cap-dependent translation and ribosome biogenesis, increasing protein synthesis and other anabolic processes. mTOR is responsive to oxidative stress and promotes the upregulation of NRF2 (Nuclear Factor Erythroid 2-Related Factor), a protein that in normal conditions is held into the cytoplasm by the negative interaction with Kelch-like ECH-associated protein 1 (KEAP1) and which is considered the master regulator of several genes involved in the oxidative homeostasis. It is unclear whether NRF2 can also modulate mTOR and the straight influences of NRF2 on mTOR/S6Ks needs to be in-depth investigated. Since KEAP1 is the most frequently mutated in lung cancers, this type of cancer is of interest to study the NRF2 pathway and the outcomes related to its modulation. Thus, using KrasLSL-G12D/+; p53flox/flox (KP) genetically engineered mouse models (GEMMs), which mimic human Kras-driven lung adenocarcinoma (LUAD) this project aims to generate KEAP1 (KPK) or NRF2 (KPN) knockout tumors in KP mice via the intratracheal infection with pSECC derived lentiviral vectors expressing sgRNAs against KEAP1 or NRF2, to assess the effects of NRF2 pathway modulations on mTOR signaling and tumor development. Furthermore, KP, KPK, and KPN mice and cell lines will be treated with mTOR inhibitors such as rapamycin to explore possible mechanisms of synthetic lethality. Our studies will provide insight into the importance of NRF2 and mTOR pathway interactions in lung cancer and determine the therapeutic potential of targeting these pathways. (AU)