Role of macrophages in the determination of liver microenvironment and progression from steatohepatitis (NASH) to hepatocellular carcinoma (HCC)

• Grant number: 24/01970-8
• Support Opportunities: Regular Research Grants
• Duration: July 01, 2024 - June 30, 2026
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Convênio/Acordo: CNPq
• Principal Investigator: William Tadeu Lara Festuccia
• Grantee: William Tadeu Lara Festuccia
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 20/04159-8 - mTORC2 and mTORC1 biology and involvement in steatosis development and progression to steatohepatitis and hepatocellular carcinoma, AP.TEM
• Associated scholarship(s): 24/11195-1 - Role of macrophages in the determination of liver microenvironment and progression from steatohepatitis (NASH) to hepatocellular carcinoma (HCC), BP.JD

Abstract

Approximately 80-90% of primary HCC cases occur as a progression from steatohepatitis (NASH), namely, in livers displaying chronic inflammation. In this study, we will address how chronic liver inflammation modulates the microenvironment favoring immune evasion and NASH progression to HCC with a special focus on the role of liver resident Kupffer cells and recruited macrophages as major determinants of these processes. For this, we will employ two mouse models that display well defined NASH to HCC progression namely: 1- mice with Pten deletion in hepatocytes, which display a diet-independent NASH to HCC progression due to enhanced hepatocyte lipid synthesis; and 2- mice with Raptor deletion in hepatocytes that develop liver tumors when fed a high fat diet and treated with carcinogen CCL4. In a first protocol, these mice will be euthanized upon either NASH or HCC for the characterization liver resident leukocytes (Kupffer Cells and recruted macrophages, neutrophils, lymphocytes etc) by FACs and RNASeq, lipid deposition and fibrotic stage, cytokine and chemokine profile, metabolite profile, inflammatory signaling through TLR4, NLRP3-inflammasome, MAPK and PI3K-mTOR pathways, lipid and glucose metabolism, mitochondrial function, oxidative stress and DNA damage. In a second protocol, both mouse models will be evaluated for the same parameters detailed in protocol 1 after macrophage depletion with clodronate 4 weeks prior to either NASH or HCC times points to investigate the role of resident and infiltrated macrophages in NASH and HCC development. By doing so, we expect to gain further insights about the critical inflammatory aspects that make the liver microenvironment prone to immune evasion and NASH progression to HCC. Such knowledge could significantly contribute to the development of novel strategies to prevent and treat HCC. (AU)