Project 2 - Fatty Liver Predisposes to Metastasis: Role of Hepatic Stellate Cells

项目 2 - 脂肪肝易于转移：肝星状细胞的作用

• 批准号: 10558481
• 负责人: EKIHIRO SEKI
• 金额: $ 31.31万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-21 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10558481
• 关键词: Acceleration; Animal Model; Biological Markers; Breast; CD44 gene; Cancer Patient; Cell Proliferation; Cells; Collagen; Colon; Colorectal; Colorectal Cancer; Data; Defense Mechanisms; Elements; Endoglin; Engraftment; Environment; Enzymes; Extracellular Matrix; Fatty Liver; Fibronectins; Growth; HAS2 gene; Health; Hepatic Stellate Cell; Hepatocyte; High Fat Diet; Human; Hyaluronic Acid; Incidence; Infiltration; Invaded; Kupffer Cells; Liver; Liver Fibrosis; Liver neoplasms; Malignant Neoplasms; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Mediating; Metastatic Neoplasm to the Liver; MicroRNAs; Molecular; Myofibroblast; Neoplasm Metastasis; Obesity; Oncogenic; Organ; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Plasma; Prevalence; Primary Neoplasm; Production; Prostate; Proteins; Reporting; Research; Resources; Risk; Rodent Model; Role; Signal Transduction; Site; Source; Specimen; Tenascin; Testing; Therapeutic; Tissues; Transgenic Mice; Travel; Tumor Promotion; Tumor Suppressor Proteins; Tumor-Derived; Visceral metastasis; Work; cancer cell; cancer type; cell type; cohort; extracellular vesicles; feeding; high risk; innovation; insight; methionine adenosyltransferase; mortality; mouse model; non-alcoholic fatty liver disease; novel; overexpression; periostin; programs; receptor; scaffold; tumor; tumor growth; tumor microenvironment

PROJECT 2: Fatty Liver Predisposes to Metastasis: Role of Hepatic Stellate Cells PROJECT SUMMARY The central hypothesis being tested by this Program project is that the normal liver has defense mechanisms to suppress metastatic growth, which are lowered by insults to the liver microenvironment to allow metastatic engraftment and expansion. Project 2 focuses on the role of fatty liver in liver metastasis, examining the hypothesis that non-alcoholic fatty liver disease (NAFLD) associates with a tumor-promoting liver microenvironment that is mediated by hepatic stellate cells (HSCs), hyaluronic acids (HAs), and hepatocyte- derived extracellular vesicles (EVs). Obesity and NAFLD are serious health concerns that increase the risk of primary cancers including liver, pancreas, colon, prostate, and breast. Fatty liver also supports liver metastasis in patients as well as in rodent models. The liver is the most frequent site for metastasis of visceral cancers such as colorectal (CRC) and pancreatic ductal adenocarcinoma (PDAC). The extent of liver metastasis is a major survival determinant for patients with these cancers as well as for those with prostate cancer (PCa). The objective of Project 2, thus, is to investigate molecular mechanism(s) underlying HSC-mediated, enhanced metastatic growth in the fatty liver environment. In liver, HSCs are precursors of liver myofibroblasts that produce extracellular matrix (ECM) components, such as HAs. Both HSCs and the ECM are elemental in supporting a liver tumor microenvironment. This research team's preliminary data show that HSC infiltration and ECM production (as evidenced by HAs) in metastatic tumors were increased in a fatty liver environment. In contrast to previous studies showing that primary tumor- derived EVs travel to the liver to create a pre-metastatic niche, we propose the innovative hypothesis that a pro-metastatic liver microenvironment is instead facilitated by non-cancerous, steatotic hepatocytes that secrete EVs containing pro-fibrogenic and oncogenic microRNAs (miRNAs). This project will examine liver metastasis in fatty liver for three different cancer types (CRC, PDAC, and PCa) via three specific aims. Aim 1 will investigate whether HSC-derived HA promotes metastatic liver tumor growth in fatty liver with HSC-specific deletion or overexpression of HA synthase 2 (Has2), in the presence of high-fat diet (HFD). Aim 2 will investigate whether HA overexpression in fatty liver promotes metastatic tumor growth via CD44, Notch1, and Yes-associated protein (YAP). Aim 3 will investigate whether fatty liver-derived EVs promote cancer metastasis to the liver by activating tumor-promoting pathways via oncogenic miRNAs. We will also seek EV-miRNAs as biomarkers to predict patients at high risk for liver metastasis. This project integrates with others in the Program by examining associations between fatty liver-mediated HAS2 overexpression and YAP (Projects 1, 3) and methionine adenosyltransferase 1A (MAT1A, Project 4).

项目2：脂肪肝易于转移：肝星细胞的作用 项目摘要 该计划项目测试的中心假设是普通肝具有防御机制 抑制转移性生长，通过对肝微环境的侮辱降低了转移 植入和扩展。项目2侧重于脂肪肝在肝转移中的作用，研究 假设非酒精性脂肪肝疾病（NAFLD）与肿瘤肝脏有关 由肝星状细胞（HSC），透明质酸（HAS）和肝细胞介导的微环境 衍生的细胞外囊泡（EV）。肥胖和NAFLD是严重的健康问题，增加了 主要癌症，包括肝脏，胰腺，结肠，前列腺和乳房。脂肪肝也支持肝转移 在患者以及啮齿动物模型中。肝脏是内脏癌转移的最常见部位 例如结直肠癌（CRC）和胰腺导管腺癌（PDAC）。肝转移的程度是 这些癌症患者以及前列腺癌（PCA）患者的主要生存决定因素。这 因此，项目2的目标是研究HSC介导的，增强的分子机制 脂肪肝环境中的转移性生长。 在肝脏中，HSC是产生细胞外基质（ECM）成分的肝肌纤维细胞的前体，例如 像这样。 HSC和ECM均为支持肝肿瘤微环境的元素。这项研究 团队的初步数据表明，HSC浸润和ECM生产（如HAS所证明） 在脂肪肝脏环境中，肿瘤增加。与以前的研究相反，原发性肿瘤 派生的电动汽车前往肝脏创建了一种预先转移的利基市场，我们提出了一种创新的假设，即 促肝微环境相反，是由非癌性脂肪性肝细胞促进的 分泌含有促纤维化和致癌microRNA（miRNA）的电动汽车。 该项目将检查三种不同癌症类型（CRC，PDAC和PCA）的脂肪肝中的肝转移 通过三个特定目标。 AIM 1将研究HSC衍生的HA是否促进转移性肝肿瘤生长 在HSC特异性缺失或HA合酶2（HAS2）的脂肪肝中，在高脂的存在下 饮食（HFD）。 AIM 2将研究脂肪肝中的HA过表达是否促进转移性肿瘤的生长 通过CD44，Notch1和与YES相关的蛋白质（YAP）。 AIM 3将调查脂肪肝衍生的电动汽车是否 通过致癌miRNA激活促进肿瘤的途径，促进肝脏转移到肝脏。我们将 还寻求EV-MIRNA作为生物标志物，以预测肝转移高风险的患者。该项目集成了 与该计划中的其他人一起检查脂肪肝介导的HAS2过表达与 YAP（项目1，3）和蛋氨酸腺基转移酶1A（MAT1A，项目4）。