Involvement of mTORC1 and Erk in metabolic reprogramming and determination of tumor microenvironment in hepatocellular carcinoma

• Grant number: 23/18351-6
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: March 30, 2024
• End date: March 29, 2025
• Field of knowledge: Biological Sciences - Physiology - General Physiology
• Principal Investigator: William Tadeu Lara Festuccia
• Grantee: Érique de Castro
• Supervisor: Marcia Haigis
• 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: 20/16656-6 - Participation of the MAPK pathway in the acceleration of hepatocellular carcinogenesis induced by the Raptor/mTORC1 deletion in hepatocytes, BP.PD

Abstract

Signaling through the mechanistic target of rapamycin complex 1 (mTORC1) pathway is increased in hepatocellular carcinoma (HCC), but paradoxically, genetic inhibition of mTORC1 via Raptor deletion in hepatocytes also promotes HCC development in conditions of liver lipid overload. We found during my postdoc (FAPESP Process 2020/16656-6) that HCC in hepatocyte mTORC1 deficient mice is in part due to an increase in the mitogen-activated protein kinase signaling in hepatocytes. Indeed, pharmacological inhibition of MEK/Erk with PD0325901 reduces the number and size of tumors in the liver of mice with mTORC1 deficiency in hepatocytes, in addition to reducing the content of TNFa and IL-6, which are important components of the tumor microenvironment. Metabolic reprogramming occurs in the tumor microenvironment favoring processes such as angiogenesis and immune tolerance, among others, that lead to immune evasion and tumor growth. Recently, Dr Marcia Haigis laboratory discovered using state-of-the-art approaches that tumor cells can secrete lactate and stimulate pyruvate metabolism in CD8+ T cells, decreasing their cytotoxicity and ability to kill tumor cells. Therefore, we propose to undertake a 1-year internship in Dr Haigis' laboratory, to test the hypothesis that MEK/Erk inhibition reduces tumor development in mTORC1 deficient mice by altering tumor metabolome and restoring immune cell ability to detect and kill tumor cells. To test this hypothesis, we propose to evaluate the metabolome of liver tumor and non-tumor areas of hepatocyte mTORC1-deficient mice treated or not with the MEK/Erk inhibitor PD0325901. Next, we will test whether metabolites altered in the tumor and serum of hepatocyte mTORC1-deficient mice treated or not with MEK/Erk inhibitor affect metabolism and function of primary CD8+ T cells in culture. Characterization of tumor microenvironment metabolome and its impact on the immune cell function can be instrumental in the development of new drugs aiming to increase the survival of patients with HCC. Undertaking an internship in Dr Haigis laboratory, which is recognized worldwide for its excellence in research, will certainly be an excellent learning experience and outstanding opportunity to advance my scientific career.