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) 是全球第三大癌症死亡原因，导致超过 700,000 人死亡 在过去三十年里，美国的肝癌发病率每年增加两倍。非酒精性肥胖症的增加。 脂肪肝病（NAFLD）和非酒精性脂肪性肝炎（NASH）越来越多地导致晚期 肝脏疾病和肝癌的发展与慢性损伤、炎症和纤维化密切相关。 患者的疾病进展和 HCC 发展，足以引发小鼠的 HCC - 表明 HCC 真正代表了“无法愈合的伤口”，尽管 HCC 可能在没有明显症状的情况下发生。 NASH 中的肝硬化，几乎所有 NASH-HCC 仍然在纤维化肝脏中发展，因此，纤维化是最严重的一种。 HCC 和 NASH-HCC 的重要但鲜为人知的危险因素此外，纤维化是主要决定因素。 NASH 的结果和大多数治疗努力都是为了减少纤维化，因此，了解 NASH 的作用。 我们和其他人之前已经证明，成纤维细胞与 NASH 中的 HCC 发展高度相关。 星状细胞（HSC）是肝脏中成纤维细胞的主要来源。该提议基于初步数据。 首次通过可靠且互补的遗传方法显示出对 HCC 的强烈促进作用 然而，虽然 HSC 在慢性肝病中的总体作用是促进肿瘤，但我们 基于此，我们的中心得出了 HSC 既可以促进又可以预防 HCC 的惊人观察。 假设细胞因子和生长因子分泌亚群（cyHSC），类似于体内的静态 HSC 健康的肝脏，预防 NASH-HCC，而高度活化的肌成纤维细胞 HSC (myHSC) 则促进 与此相关，我们还提出正常肝脏中较高比例的 cyHSC 可以提供保护。 健康状态下来自 HCC，而受损肝脏中较高比例的 myHSC 会导致疾病—— 在这里，我们试图从功能上描述 HSC 衍生的贡献。 我们将首先确定成纤维细胞和亚群特异性介质在 NASH 相关 HCC 中的作用。 通过基因耗竭和抑制方法获得 HSC 衍生的成纤维细胞，并表征 HSC 亚群 以及它们的细胞和配体-受体相互作用以及它们在单细胞疾病进展过程中的进化 RNA 测序和 CellPhoneDB 在小鼠和人类 NASH 中的作用（目标 1）我们将确定 myHSC- 的作用。 分泌介质，重点关注 I 型胶原蛋白、其受体和下游途径（目标 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 CXCL12（目标 3） 总之，拟议的研究将揭示 NASH 病理生理学的新见解。 HCC 并为 HSC 的促肿瘤和抑肿瘤功能提供证据。 不仅可以开辟新的治疗途径，针对肿瘤促进途径，同时保留或恢复 肿瘤抑制途径，而且还改变了当前 HSC 在 HCC 发展中作用的范式。