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.

肝细胞癌是全球第三大癌症死亡原因，造成70多万人死亡。 每年的死亡人数。在美国，肝细胞癌的发病率在过去30年里增加了两倍。非酒精性肥胖症的增加 脂肪肝(NAFLD)和非酒精性脂肪性肝炎(NASH)对晚期 肝脏疾病和肝细胞癌的发展。慢性损伤、炎症和纤维化与 患者的疾病进展和肝癌的发展，并足以在小鼠中引发肝癌--这表明 肝细胞癌真正代表了“一个无法愈合的伤口”。即使肝细胞癌可能在缺乏明显的 在NASH中，几乎所有的NASH-HC仍在纤维化的肝脏中发展。因此，纤维化是最严重的 肝细胞癌和非酒精性肝细胞癌的显著但最不为人所知的危险因素。此外，纤维化是一个主要的决定因素。 NASH的结果和大多数治疗努力旨在减少纤维化。因此，理解 成纤维细胞与NASH中肝细胞癌的发生发展密切相关。我们和其他人之前已经证明了肝脏 星状细胞(HSC)是肝脏成纤维细胞的主要来源。这项建议是基于初步数据 首次通过可靠和互补的遗传方法显示出对肝癌的强大促进作用 由HSC开发。然而，虽然HSC在慢性肝病中的总体效果是促进肿瘤的，但我们 令人惊讶的是，HSC对肝癌既有促进作用，又有保护作用。基于此，我们中央 假设是一个细胞因子和生长因子分泌亚群(CyHSC)，类似于静止的HSC 健康的肝脏，保护NASH-HCC，而高活性的成纤维细胞HSC(MyHSC)促进 纳什-肝癌。与此相关，我们还建议在正常肝脏中较高比例的cyHSC提供保护。 来自健康状态的肝细胞癌，而受损肝脏中较高比例的myHSC有助于疾病- 联合促进肝细胞癌的发生。在这里，我们试图从功能上表征HSC衍生的贡献 NASH相关肝细胞癌中的成纤维细胞和亚群特异性介质。我们首先要确定的是 基因耗竭和抑制方法诱导的HSC来源的成纤维细胞及其亚群特征 以及它们的细胞和配体-受体相互作用及其在疾病进展过程中的单细胞进化 小鼠和人NASH的RNA测序和CellPhoneDB(目标1)。我们将确定我的HSC的角色- 分泌性介质，主要集中在I型胶原、其受体和下游途径(AIM 2)以及 以肝细胞生长因子和CXCL12(Aim 3)为核心的cyHSC分泌介质在NASH-2中的作用 相关肝细胞癌。总之，拟议的研究将揭示对NASH的病理生理学的新见解。 为进一步研究HSC的促肿瘤和抑瘤作用提供依据。这些研究 可能不仅开辟了新的治疗途径，靶向肿瘤促进途径，同时节省或恢复 肿瘤抑制途径，但也改变了目前关于HSC在肝细胞癌发展中的作用的范式。