Project 3 - HDAC/GSK-3B/YAP signaling network in the liver metastatic microenvironment

项目3-肝转移微环境中的HDAC/GSK-3B/YAP信号网络

• 批准号: 10331759
• 负责人: STEPHEN J PANDOL
• 金额: $ 32.09万
• 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/10331759
• 关键词: Animal Model; Cell Communication; Cell physiology; Chemicals; Collaborations; Colon Carcinoma; Colorectal Cancer; Data; Environment; Enzymes; Fatty Acids; Fatty Liver; Growth; Hepatic; Hepatic Stellate Cell; High Fat Diet; Histone Deacetylase; Hyaluronic Acid; Immune; Immunologic Surveillance; Interleukin-13; Interleukin-4; Knowledge; Kupffer Cells; Liver; Malignant Neoplasms; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Medical; Metastatic Neoplasm to the Liver; Metastatic to; Modeling; Molecular Target; Mus; Neoplasm Metastasis; Outcome; Pathway interactions; Phenotype; Phosphotransferases; Play; Prevention; Process; Proteins; Regulation; Resistance; Role; Signal Pathway; Signal Transduction; Signaling Protein; System; Therapeutic; Tissues; Transforming Growth Factors; Tumor Expansion; base; cancer cell; cancer therapy; cell type; conditional knockout; design; glycogen synthase kinase 3 beta; insight; macrophage; macrophage stimulating protein; matriptase; metastasis prevention; novel; pancreatic cancer model; polarized cell; programs; prostate cancer cell; receptor; recruit; small molecule; stellate cell; translocase; tumor; tumor growth; tumor microenvironment

ABSTRACT Project 3 is designed to determine the roles of class I and II histone deacetylase (HDAC I/II), glycogen synthase kinase-3β (GSK-3β), Yes-associated protein (YAP) and downstream signaling pathways involving the macrophage-stimulating protein (MSP) and its receptor, RON (Recepteur d'Origine Nantais) kinase, in promoting cancer metastasis in the liver. The project considers these cancer cell pathways and the recruitment of hepatic stellate cells (HSCs) and Kupffer cells (macrophages in the liver) to constitute a microenvironment for enhancing the growth of the metastasis. The potential role of these pathways on cancer metastasis comes from our observations in metastasis promotion using a new chemical entity we designed to inhibit HDAC I/II and GSK-3β, two key enzymes that are overactivated in pancreatic, prostate and colorectal cancer. Further, our preliminary shows roles for HDAC I/II and GSK-3β in regulating YAP, MSP, RON and metastasis. Based on preliminary results, we propose the following specific aims: (1) to investigate the mechanisms by which HDAC and GSK-3β regulate YAP signaling in cancer cells to promote the growth of metastasis in the liver; and (2) to investigate the regulation and role of YAP signaling in HSCs for remodeling of cancer microenvironment in the liver to promote the growth of liver metastasis. In collaboration with other projects of this Program, Project 3 will study the roles of YAP and MSP/RON signaling in pancreatic, colon, and prostate cancers and determine the relationship of these signals with fatty liver and high fat diet. The outcomes of this project will significantly enhance our understanding of the mechanisms underlying the promotion of cancer metastasis to the liver, with clear insights for application of the knowledge to the prevention and treatment of cancer metastasis.

抽象的 项目3旨在确定I级和II级Hisstone脱乙酰基酶（HDAC I/II）的作用， 糖原合酶激酶-3β（GSK-3β），是相关蛋白（YAP）和下游信号传导 涉及巨噬细胞刺激蛋白（MSP）及其受体RON的途径（Recepteur） D'Origine Nantais）激酶，在促进肝脏中的癌症转移方面。该项目认为这些 癌细胞途径和肝星状细胞（HSC）和库普弗细胞的募集 （肝脏中的巨噬细胞）构成一个微环境，以增强 转移。这些途径在癌症转移中的潜在作用来自我们 使用我们旨在抑制HDAC的新化学实体进行转移促进的观察结果 I/II和GSK-3β，两个关键酶，在胰腺，前列腺和结直肠酯中过度活跃 癌症。此外，我们的初步显示了HDAC I/II和GSK-3β在调节性YAP，MSP， 罗恩和转移。 基于初步结果，我们提出以下特定目的：（1）研究 HDAC和GSK-3β调节癌细胞中YAP信号的机制以促进 肝脏转移的生长； （2）调查YAP信号传导的调节和作用 HSC用于在肝脏中重塑癌症微环境以促进肝脏的生长 转移。与该计划的其他项目合作，项目3将研究 胰腺，结肠和前列腺癌中的YAP和MSP/RON信号传导，并确定 这些信号与脂肪肝和高脂饮食的关系。这个项目的结果将 显着增强了我们对促进癌症基础机制的理解 向肝脏转移，并有明确的见解将知识应用于预防和 治疗癌症转移。