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

项目2：脂肪肝易发生转移：肝星状细胞的作用 项目总结 该计划项目正在检验的中心假设是，正常肝脏具有防御机制 抑制转移性生长，通过对肝脏微环境的侮辱来降低转移性生长 嫁接和扩张。项目2集中在脂肪肝在肝转移中的作用，检查 非酒精性脂肪性肝病(NAFLD)与促进肿瘤的肝脏相关的假说 由肝星状细胞(HSCs)、透明质酸(HAS)和肝细胞介导的微环境 衍生的细胞外小泡(EVS)。肥胖和非酒精性脂肪肝是严重的健康问题，会增加患上 原发性癌症包括肝癌、胰腺癌、结肠癌、前列腺癌和乳腺癌。脂肪肝也支持肝脏转移 在病人和啮齿动物模型中也是如此。肝脏是内脏癌最常见的转移部位。 如结直肠癌(CRC)和胰腺导管腺癌(PDAC)。肝转移的范围是 这些癌症患者以及前列腺癌(PCa)患者的主要生存决定因素。这个 因此，项目2的目标是研究HSC介导的增强的分子机制(S) 脂肪肝环境中的转移性生长。 在肝脏中，HSC是肝脏肌成纤维细胞的前体细胞，产生细胞外基质(ECM)成分，如 就像以前一样。HSCs和ECM都是支持肝脏肿瘤微环境的基本细胞。这项研究 研究小组的初步数据显示，在转移性肿瘤中，HSC的渗透和ECM的产生(HAS证明) 在脂肪肝环境中，肿瘤增加。与之前的研究表明原发肿瘤- 衍生的EV进入肝脏创造转移前的生态位，我们提出了一个创新的假设，即 促进转移的肝脏微环境由非癌性、脂肪变性的肝细胞促进，这些细胞 分泌含有促纤维化和致癌microRNAs(MiRNAs)的EV。 本项目将研究三种不同癌症类型(结直肠癌、顺铂和前列腺癌)脂肪肝的肝转移情况。 通过三个具体目标。目的1研究HSC来源的HA是否促进转移性肝肿瘤的生长 在HSC特异性缺失或过度表达HA合成酶2(Has2)的脂肪肝患者中，存在高脂肪 饮食(HFD)。目的2将研究脂肪肝中HA的过度表达是否促进转移瘤的生长 通过CD44、Notch1和YAP相关蛋白(YAP)。AIM 3将调查脂肪肝衍生的EV 通过致癌的miRNAs激活促进肿瘤的通路，从而促进肿瘤转移到肝脏。我们会 同时寻找EV-miRNAs作为预测肝转移高危患者的生物标志物。该项目集成了 通过研究脂肪肝介导的HAS2过度表达和 YAP(项目1、3)和蛋氨酸腺苷转移酶1A(MAT1A，项目4)。

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).