Determinants of Liver Metastasis

肝转移的决定因素

• 批准号: 10524071
• 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: 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/10524071
• 关键词: Address; Adopted; Animal Model; Bioinformatics; Biometry; CD36 gene; Cancer Etiology; Carcinoma; Cessation of life; Clinical; Collaborations; Colon; Colon Carcinoma; Complement; Data; Dietary Intervention; Doctor of Philosophy; Effectiveness; Endoglin; Engraftment; Ensure; Environment; Epithelial; Extracellular Matrix; Fatty Liver; Fatty acid glycerol esters; Glutamate-Ammonia Ligase; Glutamine; Goals; Growth; HDAC3 gene; Health Personnel; Healthcare Systems; Hepatic; Hepatic Stellate Cell; Hepatocyte; High Fat Diet; Histone Deacetylase; Home; Human; Hyaluronic Acid; In Vitro; Institution; Investigation; Kupffer Cells; Liver; Los Angeles; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Mediating; Medical center; Metabolic; Metastatic Neoplasm to the Liver; MicroRNAs; Modeling; Molecular; Morbidity - disease rate; Mus; Neoplasm Circulating Cells; Neoplasm Metastasis; Obesity; Oncogenic; Pancreas; Pathway interactions; Patients; Pharmacology; Phenotype; Prevalence; Primary Neoplasm; Prostate; Proteins; Publishing; Regulation; Research; Research Personnel; Resistance; Resources; Role; Signal Pathway; Signal Transduction; Signaling Protein; Specimen; System; Terminal Disease; Testing; Tissues; Tumor Expansion; Tumor-Derived; United States; Work; base; cancer cell; cancer type; endoplasmic reticulum stress; extracellular vesicles; falls; glycogen synthase kinase 3 beta; human tissue; innovation; innovative technologies; liver development; macrophage; methionine adenosyltransferase; mortality; mouse model; non-alcoholic fatty liver disease; novel therapeutic intervention; programs; prostate cancer metastasis; recruit; saturated fat; success; tool; tumor; tumor growth; tumor microenvironment

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.

项目名称：肝转移的决定因素 项目摘要 肝转移预示着许多癌症的绝症，并且是癌症死亡的主要原因 美国。目前还没有专门针对肝转移机制的综合研究计划。 虽然在某些癌症类型（如胰腺癌和结肠癌）中很常见，但转移不太常见，但发生率很高 其他癌症类型（如前列腺癌）呈恶性。我们计划的长期目标是 了解并解决结肠、胰腺和肝转移的共同和独特的驱动因素 前列腺原发肿瘤类型。四个综合项目已发表的工作和初步数据表明 四个关键分子信号轴在介导肝转移中的关键作用，通过可能的机制 常见于许多原发性肿瘤类型。为了补充这种机械专业知识，该计划汇集了 不同肿瘤类型和肝脏微环境模型的临床专业知识。 该合作项目共同研究了正常肝组织本质上具有抑制性的假设 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 抑制器。项目 1 探索获取能够实现循环饱和脂肪转移的特征 以及随后肝细胞和癌上皮细胞中的内皮糖蛋白信号传导。肝脏的促转移作用 项目 2 研究了星状细胞 (HSC) 衍生的透明质酸在非酒精性脂肪肝疾病中的作用。 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 (YAP) 和下游信号通路对创建促转移肝脏的贡献 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 的丧失到促癌的 MAT2A 和 MAT2B 表达升高。经过 通过检查这四个交叉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发展因素的了解 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 研究人员的工作重点是不同肿瘤模型肝转移的共同机制 （前列腺、结肠和胰腺）。该计划采用独特的方法，调查正常的作用 肝脏微环境并利用每个项目团队的丰富专业知识以及必要资源， 包括解决信号轴的药理学方法、与医疗保健提供者的合作 通过人体组织标本和创新技术来验证动物模型中的发现 并分析转移因素，包括循环肿瘤细胞和细胞外囊泡。顺利完成 该计划将建立肝转移的新范例并测试新的治疗策略。