Determinants of Liver Metastasis

肝转移的决定因素

• 批准号: 10701208
• 负责人: Neil A. Bhowmick
• 金额: $ 12.38万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10701208
• 关键词: Determinants; Liver; Metastasis

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.

程序标题：肝转移的决定因素 程序摘要 肝转移表明许多癌症的绝症，是癌症死亡的主要原因 美国。目前尚无致力于肝转移机制的综合研究计划。 虽然在某些癌症类型（例如胰腺和结肠）中常见，但转移却不太常见，但高度很高 其他癌症类型（例如前列腺癌）中的恶性肿瘤。我们计划的长期目标是 了解并解决Colon，Pancreas和 前列腺原发性肿瘤类型。来自四个集成项目的已发表工作和初步数据指向 四个关键分子信号轴的关键作用在介导肝转移中，通过机制可能 在许多原发性肿瘤类型中常见。为了完成此机械专业知识，该计划组装 不同肿瘤类型和肝微环境模型的临床专业知识。 该协作计划一起研究了正常肝组织本质上是抑制性的假设 转移性肿瘤膨胀，除非肝微环境改变导致转移性的损失 项目1探讨了能够从循环饱和脂肪中转移的特征的获取 并随后在肝细胞和癌症上皮中发出内ogn信号。肝的亲迁移影响 在项目2中检查了非酒精性脂肪肝疾病中星状细胞（HSC）衍生的透明质酸。 为了激活HSC和巨噬细胞的亲癌表型，项目3研究了调节和 与YES相关蛋白（YAP）和下游信号通路的贡献 微环境。项目4研究蛋白腺基转移酶（MAT）蛋白在肝脏中的作用 从保护性MAT1A的损失到MAT2A和MAT2B的升高表达的转移。经过 检查这四个相交的信号通路并比较跨模型的发现，该程序将 增强了对肝微环境和肿瘤中因素的当前理解，使得开发 肝转移。 该计划将肝脏和癌症病理学领域的基本专业知识分配，代表了第一个多种多样的 研究者的努力重点介绍了来自不同肿瘤模型的肝转移的常见机制 （前列腺，结肠和胰腺）。该计划采用了一种独特的方法，调查了正常的作用 肝微环境和利用每个项目团队的实质专业知识以及基本资源， 包括解决信号轴的药物学方法，与医疗保健提供者的合作伙伴关系 通过人体组织标本和创新技术验证动物模型中的发现 并分析转移性因素，包括循环肿瘤细胞和细胞外蔬菜。成功完成 该计划将在肝转移中建立新的范式，并测试新颖的治疗策略。