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：脂肪肝易发生转移：肝星状细胞的作用 项目摘要 这个项目的核心假设是正常的肝脏有防御机制 以抑制转移性生长，其通过对肝脏微环境的损害而降低， 移植和扩展。项目2关注脂肪肝在肝转移中的作用， 非酒精性脂肪性肝病（NAFLD）与促肿瘤肝脏相关的假设 微环境是由肝星状细胞（HSC），透明质酸（HA）和肝细胞介导的。 衍生的细胞外囊泡（EV）。肥胖和NAFLD是严重的健康问题， 原发性癌症包括肝癌、胰腺癌、结肠癌、前列腺癌和乳腺癌。脂肪肝也支持肝转移 在病人和啮齿动物模型中。肝脏是内脏癌最常见的转移部位 如结肠直肠癌（CRC）和胰腺导管腺癌（PDAC）。肝转移的程度是一个 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。的 因此，项目2的目的是研究HSC介导的，增强的 脂肪肝环境中的转移性生长。 在肝脏中，HSC是肝肌成纤维细胞的前体，肝肌成纤维细胞产生细胞外基质（ECM）组分，如 作为哈。HSC和ECM都是支持肝肿瘤微环境的基本要素。本研究 研究小组的初步数据显示，在转移性肝癌中，HSC浸润和ECM的产生（如HA所证明的） 肿瘤在脂肪肝环境中增加。与先前的研究表明原发性肿瘤- 衍生的电动汽车旅行到肝脏，创造一个转移前的生态位，我们提出了创新的假设， 促转移肝微环境反而由非癌性脂肪变性肝细胞促进， 分泌含有促纤维化和致癌微小RNA（miRNAs）的EV。 该项目将研究三种不同癌症类型（CRC，PDAC和PCa）的脂肪肝肝转移 三个具体目标。目的1将研究HSC衍生的HA是否促进转移性肝肿瘤的生长 在HSC特异性HA合成酶2（Has 2）缺失或过表达的脂肪肝中，在高脂血症存在下， 饮食（HFD）。目的2探讨HA在脂肪肝中的过表达是否促进转移性肿瘤的生长 通过CD 44、Notch 1和Yes相关蛋白（雅普）。目的3将研究脂肪肝衍生的EV是否 通过致癌miRNAs激活肿瘤促进途径，促进癌症向肝脏转移。我们将 也寻求EV-miRNAs作为生物标志物来预测肝转移的高风险患者。该项目整合了 通过检查脂肪肝介导的HAS 2过表达与 雅普（项目1，3）和甲硫氨酸腺苷转移酶1A（MAT 1A，项目4）。