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: 10454375
• 负责人: Robert F. Schwabe
• 金额: $ 51.51万
• 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/10454375
• 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; 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; fatty liver disease; 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）是全世界癌症死亡的第三大原因，导致超过700，000人死亡。 每年死亡。在美国，HCC的发病率在过去三十年中增加了两倍。肥胖、非酒精性 脂肪性肝病（NAFLD）和非酒精性脂肪性肝炎（NASH）越来越多地导致晚期 肝脏疾病和HCC发展。慢性损伤、炎症和纤维化与 患者的疾病进展和HCC发展，并足以在小鼠中触发HCC-这表明， HCC真正代表了“无法愈合的伤口”。即使HCC可能在没有明显的 在NASH中的肝硬化中，几乎所有NASH-HCC仍然在纤维化肝脏中发展。因此，纤维化是最常见的 HCC和NASH-HCC的突出但最不了解的风险因素。此外，纤维化是一个主要的决定因素， NASH中的大多数治疗努力旨在减少纤维化。因此，理解 成纤维细胞在NASH的HCC发展中是高度相关的。我们和其他人以前已经表明，肝 星状细胞（HSC）是肝脏中成纤维细胞的主要来源。该提案基于初步数据 通过可靠和互补的遗传方法首次显示出HCC的强烈促进作用 由HSC开发。然而，尽管HSC在慢性肝病中的总体作用是促进肿瘤，我们 发现HSC可以促进和保护HCC。基于此，我们的中央 一种假说是，细胞因子和生长因子分泌亚群（cyHSC），类似于静止期HSC， 健康肝脏保护免于NASH-HCC，而高度活化的肌成纤维细胞HSC（myHSC）促进 NASH-HCC。与此相关，我们还建议正常肝脏中较高百分比的cyHSC提供保护 在健康状态下，myHSC从HCC中分离出来，而在受伤的肝脏中，myHSC的百分比较高，这有助于疾病的发生- 促进HCC的发展。在这里，我们试图从功能上表征HSC衍生的贡献， 成纤维细胞和亚群特异性介质在NASH相关HCC中的作用。我们将首先确定 通过遗传耗竭和抑制方法，对HSC来源的成纤维细胞进行鉴定，并表征HSC亚群 以及它们的细胞和配体-受体相互作用和它们在疾病进展过程中通过单细胞 在鼠和人NASH中的RNA测序和CellPhoneDB（目的1）。我们将决定我的HSC的作用- 分泌的介质，重点是I型胶原蛋白，其受体和下游途径（Aim 2）以及 cyHSC分泌的介质在NASH中的作用，重点是肝细胞生长因子和CXCL 12（Aim 3）， 相关HCC总之，拟议的研究将揭示NASH病理生理学的新见解， 并为HSC的促癌和抑癌功能提供了证据。这些研究 不仅可以开辟新的治疗途径，靶向肿瘤促进途径，同时保留或恢复 肿瘤抑制途径，而且还改变了目前关于HSC在HCC发展中的作用的范式。