Determinants of Liver Metastasis

肝转移的决定因素

• 批准号: 10558473
• 负责人: Neil A. Bhowmick
• 金额: $ 178.45万
• 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/10558473
• 关键词: Acceleration; Address; Adopted; Animal Model; Bioinformatics; Biometry; CD36 gene; Cancer Etiology; Carcinoma; Cessation of life; Clinical; Collaborations; Colon; Colon Carcinoma; Complement; Data; Dietary Intervention; Disparate; Doctor of Philosophy; Effectiveness; Endoglin; Engraftment; Ensure; Environment; Epithelium; Extracellular Matrix; Fatty Liver; Fatty acid glycerol esters; Glutamate-Ammonia Ligase; Glutamine; Goals; Growth; 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; Macrophage; Malignant - descriptor; Malignant Neoplasms; 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; 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 Promotion; Tumor-Derived; United States; Work; cancer cell; cancer type; endoplasmic reticulum stress; extracellular vesicles; falls; glycogen synthase kinase 3 beta; human tissue; innovation; innovative technologies; liver development; methionine adenosyltransferase; mortality; mouse model; non-alcoholic fatty liver disease; novel therapeutic intervention; permissiveness; pharmacologic; 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.

项目标题：肝转移的决定因素