Determinants of Liver Metastasis

标题：肝转移的决定因素 中文摘要 肝转移表明许多癌症的晚期疾病，并且是癌症死亡的主要原因。 美国的目前还没有专门针对肝转移机制的综合研究计划。 虽然常见于某些癌症类型（如胰腺癌和结肠癌），但转移不太常见，但高度 其他类型的恶性肿瘤（如前列腺癌）。我们计划的长期目标是 了解并解决结肠，胰腺和肝脏转移的共同和独特的驱动因素， 前列腺原发肿瘤类型已发表的工作和四个综合项目的初步数据表明， 四个关键分子信号传导轴在介导肝转移中的关键作用，通过可能的机制， 常见于许多原发性肿瘤类型。为了补充这种机械的专业知识，该计划组装 不同肿瘤类型和肝脏微环境模型的临床专业知识。 这个合作项目共同研究了正常肝组织固有抑制性的假设， 转移性肿瘤扩张，除非肝脏微环境的改变导致转移性肿瘤的丧失。 抑制剂项目1探讨了获得的功能，使转移从循环饱和脂肪 以及随后在肝细胞和癌上皮中的内皮糖蛋白信号传导。肝细胞癌的促转移作用 星状细胞（HSC）衍生的透明质酸在非酒精性脂肪肝疾病中的研究在项目2中进行。思想 为了激活HSC和巨噬细胞的促癌表型，项目3研究了调控和 yes相关蛋白（雅普）和下游信号通路对产生促转移性肝脏的贡献 微环境项目4研究蛋氨酸腺苷转移酶（MAT）蛋白在肝脏中的作用 转移，从保护性MAT1A的丧失到MAT2A和MAT2B的促癌表达升高。通过 研究这四个交叉的信号通路，并比较不同模型的结果，该计划将 增加目前对肝脏微环境和肿瘤中允许发展的因素的理解 肝转移 该计划结合了肝脏和癌症病理学领域的基本专业知识，代表了第一个多学科的 研究者努力集中在不同肿瘤模型肝转移的共同机制 （前列腺、结肠和胰腺）。该方案采用了一种独特的方法，调查正常人的作用， 肝脏微环境和利用每个项目团队的大量专业知识沿着基本资源， 包括解决信号轴的药理学手段，与医疗保健提供者的合作， 通过人体组织标本在动物模型中验证研究结果， 并分析包括循环肿瘤细胞和细胞外囊泡在内的转移因素。成功完成 该计划的一部分将建立新的肝转移范例，并测试新的治疗策略。

PROGRAM TITLE: Determinants of Liver Metastasis PROGRAM ABSTRACT Liver metastasis indicates a terminal illness for many cancers and is a leading cause of cancer death in the United States. There is currently no integrated research program devoted to mechanisms of liver metastasis. While common in certain cancer types (such as pancreas and colon), metastasis is less common but highly malignant in other cancer types (such as prostate cancer). The long-term goal of our Program is to understand and address the shared and unique drivers of liver metastasis in colon, pancreas, and prostate primary tumor types. Published work and preliminary data from the four integrated projects point to key roles for four critical molecular signaling axes in mediating liver metastasis, through mechanisms likely common across many primary tumor types. To complement this mechanistic expertise, this Program assembles clinical expertise across different tumor types and liver microenvironment models. Together, this collaborative Program investigates the hypothesis that normal liver tissue is inherently suppressive of metastatic tumor expansion, unless alterations in the liver microenvironment result in the loss of metastatic suppressors. Project 1 explores the acquisition of features that enable metastasis from circulating saturated fat and subsequent endoglin signaling in hepatocytes and cancer epithelia. The pro-metastatic impact of hepatic stellate cell (HSC)-derived hyaluronic acids in non-alcoholic fatty liver disease is examined in Project 2. Thought to activate pro-cancer phenotypes of HSCs and macrophages, Project 3 investigates the regulation and contribution of yes-associated protein (YAP) and downstream signaling pathways to create a pro-metastatic liver microenvironment. Project 4 investigates the roles of methionine adenosyltransferase (MAT) proteins in liver metastasis, from the loss of protective MAT1A to the pro-cancer elevated expression of MAT2A and MAT2B. By examining these four intersecting signaling pathways and comparing findings across models, this Program will augment current understanding of factors in the liver microenvironment and tumor that permit the development of liver metastases. This Program unites essential expertise in the fields of liver and cancer pathobiology to represent the first multi- investigator effort focused on common mechanisms involved in liver metastasis from disparate tumor models (prostate, colon, and pancreas). The Program adopts a unique approach, investigating the role of the normal liver microenvironment and leveraging each project team’s substantial expertise along with essential resources, including pharmacologic means of addressing the signaling axes, partnerships with healthcare providers to validate the findings in animal models through human tissue specimens, and innovative technology to isolate and analyze metastatic factors including circulating tumor cells and extracellular vesicles. Successful completion of the Program will establish new paradigms in liver metastasis and test novel therapeutic strategies.