Determinants of Liver Metastasis

计划标题：肝转移的决定因素 程序摘要 肝转移是许多癌症的晚期疾病，也是导致癌症死亡的主要原因。 美国。目前还没有专门研究肝转移机制的综合研究计划。 虽然在某些癌症类型(如胰腺和结肠癌)中很常见，但转移较少，但很高。 在其他癌症类型(如前列腺癌)中是恶性的。我们计划的长期目标是 了解和解决共同的和独特的肝转移的驱动因素在结肠癌、胰腺和 前列腺癌原发肿瘤类型。发表的工作和来自四个综合项目的初步数据表明 四个关键分子信号轴在介导肝转移中的关键作用，可能通过机制 在许多原发肿瘤类型中常见。为了补充这种机械专业知识，本程序汇编了 跨不同肿瘤类型和肝脏微环境模型的临床专业知识。 这一合作项目共同研究了正常肝组织固有抑制的假说 转移性肿瘤扩大，除非肝脏微环境的改变导致转移的丧失 抑制者。项目1探索获得使循环饱和脂肪发生转移的特征。 以及随后肝细胞和癌细胞中的endoglin信号转导。肝细胞癌的促转移作用 项目2检查了非酒精性脂肪性肝病中星状细胞(HSC)衍生的透明质酸。 为了激活HSCs和巨噬细胞的致癌表型，项目3研究了HSCs和巨噬细胞的调控和 YAP及其下游信号通路在促进肝转移中的作用 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，从失去保护性的MAT1A到癌前的MAT2A和MAT2B的表达升高。通过 检查这四条交叉的信号通路，并比较不同模型的结果，该计划将 增强目前对肝脏微环境和肿瘤中允许发生的因素的了解 肝脏转移的可能性。 该计划联合了肝脏和癌症病理生物学领域的基本专业知识，代表了第一个多学科的 研究人员致力于从不同的肿瘤模型研究涉及肝转移的常见机制 (前列腺、结肠和胰腺)。该计划采用了一种独特的方法，调查正常 肝脏微环境，并利用每个项目团队的大量专业知识和基本资源， 包括解决信号轴的药物手段，与医疗保健提供者的合作伙伴关系 通过人体组织样本和创新技术在动物模型中验证这一发现 并分析包括循环肿瘤细胞和细胞外小泡在内的转移因素。成功完成 该计划的实施将建立肝转移的新范例，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.