Tumor-promoting and tumor-suppressive roles of Hepatic Stellate Cell Subpopulations in NASH-HCC

肝星状细胞亚群在 NASH-HCC 中的促肿瘤和抑肿瘤作用

• 批准号: 10278434
• 负责人: Robert F. Schwabe
• 金额: $ 53.5万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-20 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10278434
• 关键词: Ablation; Affect; CXCL12 gene; Cancer Etiology; Cessation of life; Cholangiocarcinoma; Chronic; Cirrhosis; Collagen Receptors; Collagen Type I; Data; Development; Disease; Disease Progression; Environment; Evolution; Extracellular Matrix; Fatty Liver; Fibroblasts; Fibrosis; Functional disorder; Genetic; Goals; Growth Factor; HGF gene; Hepatic; Hepatic Stellate Cell; Hepatocarcinogenesis; Hepatocyte; Human; Immunity; Incidence; Inflammation; Injury; Ligands; Link; Liver; Liver Fibrosis; Liver diseases; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of pancreas; Mediating; Mediator of activation protein; Mus; Myofibroblast; Obesity; Outcome; Pathway interactions; Patients; Prevention; Primary carcinoma of the liver cells; Production; Regulation; Risk; Risk Factors; Role; Signal Transduction; Source; Therapeutic; Time; base; cell type; chronic liver disease; chronic liver injury; cytokine; genetic approach; improved; insight; liver cell proliferation; liver injury; mortality; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel therapeutics; premalignant; receptor; response; single-cell RNA sequencing; targeted treatment; therapeutic target; tumor; tumor microenvironment; viral liver disease; wound

Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide, causing over 700,000 deaths annually. In the US, HCC rates have tripled in the last three decades. The rise in obesity, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is increasingly contributing to advanced liver disease and HCC development. Chronic injury, inflammation and fibrosis are strongly associated with disease progression and HCC development in patients and sufficient to trigger HCC in mice - suggesting that HCC truly represents “a wound that does not heal”. Even though HCC may develop in the absence of overt cirrhosis in NASH, almost all NASH-HCCs still develop in fibrotic livers. Hence, fibrosis is one of the most prominent but least understood risk factors for HCC and NASH-HCC. Moreover, fibrosis is a main determinant of outcomes and most therapeutic efforts in NASH aim to reducing fibrosis. Hence, understanding the role of fibroblasts in HCC development in NASH is highly relevant. We and others have previously shown that hepatic stellate cells (HSC) are the main source of fibroblasts in the liver. This proposal is based on preliminary data showing for the first time by reliable and complementary genetic approaches a strong promotion of HCC development by HSC. However, while the overall effect of HSC in chronic liver disease is tumor-promoting, we made the striking observation that HSC can both promote and protect from HCC. Based on this, our central hypothesis is that a cytokine- and growth-factor secreting subpopulation (cyHSC), resembling quiescent HSC in the healthy liver, protect from NASH-HCC whereas highly activated myfibroblastic HSC (myHSC) promote NASH-HCC. Linked to this, we also propose the higher percentage of cyHSC in normal liver provide protections from HCC in the healthy state, whereas the higher percent of myHSC in injured livers contribute to disease- associated promotion of HCC. Here, we seek to functionally characterize the contribution of HSC-derived fibroblasts and subpopulation-specific mediators in NASH-associated HCC. We will first determine the role of HSC-derived fibroblasts by genetic depletion and inhibition approaches, and characterize HSC subpopulations and their cellular and ligand-receptor interactions and their evolution during disease progression by single cell RNA-sequencing and CellPhoneDB in murine and human NASH (Aim 1). We will determine the role of myHSC- secreted mediators, focusing on type I collagen, its receptors and downstream pathways (Aim 2) as well as the role of cyHSC-secreted mediators, focusing on hepatocyte growth factor and CXCL12 (Aim 3), in NASH- associated HCC. Together, the proposed studies will reveal novel insights into the pathophysiology of NASH- HCC and provide evidence for tumor-promoting as well as tumor-suppressive functions of HSC. These studies may not only open up new therapeutic avenues, targeting tumor-promoting pathways while sparing or restoring tumor-suppressive pathways, but also shift current paradigms on the role of HSC in HCC development.

肝细胞癌（HCC）是全球癌症死亡的第三大原因，死亡人数超过70万