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: 10654714
• 负责人: Robert F. Schwabe
• 金额: $ 50.19万
• 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/10654714
• 关键词: Ablation; Affect; Cancer Etiology; Cell Count; Cell secretion; Cessation of life; Cholangiocarcinoma; Chronic; Cirrhosis; Collagen Receptors; Collagen Type I; Data; Development; Disease; Disease Progression; Environment; Evolution; Extracellular Matrix; 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; Mus; Myofibroblast; Obesity; Outcome; Pathway interactions; Patients; Prevention; Primary carcinoma of the liver cells; Production; Regulation; Risk; Risk Factors; Role; Signal Transduction; Source; Stromal Cell-Derived Factor 1; Therapeutic; Therapeutically Targetable; Time; Tumor Promotion; cell type; chronic liver disease; chronic liver injury; cytokine; fatty liver disease; genetic approach; improved; insight; liver cell proliferation; liver injury; mortality; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel therapeutics; premalignant; protective pathway; receptor; response; single-cell RNA sequencing; targeted treatment; 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）是全球癌症死亡率的第三大主要原因，造成超过70万 每年死亡。在美国，HCC利率在过去三十年中增加了两倍。肥胖症的兴起，非酒精性 脂肪肝病（NAFLD）和非酒精性脂肪性肝炎（NASH）越来越有助于晚期 肝病和HCC发育。慢性损伤，感染和纤维化与 患者的疾病进展和HCC发育足以触发小鼠的HCC - 表明 HCC确实代表了“无法愈合的伤口”。即使HCC可能在没有公开的情况下发展 纳什（Nash）的肝硬化，几乎所有纳什 - HCC在纤维化生活中仍会发展。因此，纤维化是最多的 HCC和NASH-HCC的突出但最少了解的危险因素。此外，纤维化是主要的确定剂 NASH的结果和大多数治疗努力旨在减少纤维化。因此，了解 NASH的HCC开发中的成纤维细胞非常相关。我们和其他人以前已经表明了肝 星状细胞（HSC）是肝中成纤维细胞的主要来源。该建议基于初步数据 首次通过可靠而完整的遗传方法展示了强烈的HCC HSC的开发。但是，尽管HSC在慢性肝病中的总体影响是肿瘤促进的，但我们 令人惊讶的是，HSC既可以促进和保护HCC。基于此，我们的中央 假设是细胞因子和生长因子分泌亚群（CYHSC），类似于静止的HSC 健康肝脏，防止NASH-HCC，而高度激活的MyFibroblastic HSC（MYHSC）促进 NASH-HCC。与此相关的是，我们还提出了正常肝脏中CYHSC的较高百分比提供保护措施 从健康状态下的HCC，而受伤生命中MYHSC的百分比较高，导致疾病 - 相关促进HCC。在这里，我们试图在功能上表征HSC衍生的贡献 NASH相关的HCC中的成纤维细胞和亚群特异性介质。我们将首先确定 通过基因部署和抑制方法，HSC衍生的成纤维细胞，并表征HSC亚群 它们的细胞和配体 - 受体相互作用及其在疾病进展过程中的演变 鼠和人纳什（AIM 1）中的RNA测序和细胞培训。我们将确定myhsc-的作用 分泌的调解员，专注于I型胶原蛋白，其接收器和下游途径（AIM 2）以及 CYHSC分泌的介体的作用，重点是肝细胞生长因子和CXCL12（AIM 3），在NASH-中 关联的HCC。拟议的研究共同揭示了对NASH-的病理生理学的新见解。 HCC并提供了HSC的肿瘤促进以及肿瘤抑制功能的证据。这些研究 可能不仅可以打开新的治疗途径，针对促进肿瘤的途径，同时进行或恢复 肿瘤抑制途径，但也改变了当前对HSC在HCC发育中的作用的范例。