PROJECT 4: Targeting Methionine Adenosyltransferases in Liver Metastasis

项目 4：针对肝转移中的蛋氨酸腺苷转移酶

基本信息

批准号：
10558487
负责人：
Shelly Chi-Loo Lu
金额：
$ 42.55万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10558487
关键词：
Anabolism Animal Model BCL1 Oncogene Cancer Cell Growth Catalytic Domain Cell Proliferation Cell Survival Colon Carcinoma Complex Data Databases Defense Mechanisms Disseminated Malignant Neoplasm Down-Regulation Education Endoglin Enzymes FOXM1 gene Fatty Liver Gene Expression Genes Growth Hepatic Hepatocyte Homing Human Hyaluronic Acid In Vitro Individual Infiltration Invaded Knock-out Knockout Mice Liver Liver diseases MEKs Malignant Neoplasms Malignant neoplasm of pancreas Malignant neoplasm of prostate Mammals Measures Mediating Metastatic Neoplasm to the Liver MicroRNAs Molecular Mus Neoplasm Metastasis Oncogenes Oncoproteins Pathway interactions Patients Plasma Polyamines Predisposition Primary carcinoma of the liver cells Proteins Ras/Raf Regulation Resources Role S-Adenosylhomocysteine S-Adenosylmethionine Serum Signal Transduction Site Specimen Steatohepatitis Testing Therapeutic Tissues Transgenic Mice Tumor Suppressor Proteins Up-Regulation cancer cell cell motility cofactor colon cancer metastasis effective therapy extracellular vesicles falls fatty liver disease in vivo inhibitor insight metabolome methionine adenosyltransferase migration mouse model non-alcoholic fatty liver disease novel novel marker novel therapeutics overexpression patient derived xenograft model prevent programs scaffold synergism transcription factor tumor

项目摘要

PROJECT 4: Targeting Methionine Adenosyltransferases in Liver Metastasis ABSTRACT A key central hypothesis for this Program is that the normal liver has defense mechanisms to suppress metastatic growth. Project 4 is focused on the role of methionine adenosyltransferase (MAT) proteins, with MAT1A defending against liver metastasis, while MAT2A and MAT2B break down this defense. MAT catalyzes the formation of S-adenosylmethionine (SAMe), the methyl donor. The MAT1A and MAT2A genes encode MAT α1 and α2 catalytic subunits, respectively; a third gene, MAT2B, encodes the β subunit that regulates the MAT2A- encoded enzyme. MAT1A, expressed in normal liver, is downregulated in liver diseases, whereas MAT2A and MAT2B, expressed in non-hepatic tissues, are overexpressed in multiple human cancers. Preliminary data show that Mat1a knockout (KO) mice are highly sensitized to develop liver metastasis and release extracellular vesicles that contain oncoproteins; whereas MAT2A/MAT2B have a reciprocal inhibition interplay with metastasis-inhibiting tumor suppressor miRNAs miR-34a and miR-34b, but have a positive feed-forward loop with the metastasis-promoting oncogene Forkhead box M1 (FOXM1). In contrast, MAT1A and FOXM1 negatively regulate each other. Project 4 examines the effect of three molecules that target these interplays to inhibit liver metastasis: SAMe; its metabolite methylthioadenosine (MTA); and the FOXM1 inhibitor FDI-6. This project tests the hypothesis that high MAT2A/2B expression in cancer cells enhances liver metastasis by lowering hepatic MAT1A, and that SAMe, MTA, and FDI-6 inhibit liver metastasis in part by targeting MAT proteins. Importantly, human livers with metastatic cancers have lower MAT1A expression and the GEO database shows metastatic colon, pancreatic and prostate cancers have higher MAT2A/2B expression. Core B will provide human specimens and animal models to examine these MAT proteins in liver metastases from colon, pancreas, and prostate cancers over three specific aims: Aim 1. Examine the role of hepatic MAT1A expression in liver metastasis. This aim will test the hypothesis that loss of MAT1A alters extracellular vesicle content released by the liver to enhance metastatic growth. Aim 2. Determine if MAT proteins expressed by the cancer influence liver metastasis. This aim will elucidate the mechanisms responsible for MAT2A/MAT2B-mediated regulation of miR-34a/b and FOXM1, and examine whether higher MAT2A/2B expression in cancer cells enhance liver metastasis. Aim 3. Examine mechanisms and therapeutic potential of SAMe, MTA, and FDI-6 in liver metastasis. This aim will assess the effects of these three molecules (individually and combined) on cancer cell migration and invasion in vitro. The best therapy will be verified in vivo using mouse models and orthotopic patient-derived xenografts established using tissues from patients with liver metastasis. Project 4 synergizes with: Project 1, as endoglin/BMP signaling activates FOXM1, Project 2, as MAT1A expression falls in fatty liver and Mat1a KO livers have higher hyaluronic acid; and Project 3, as Metavert lowers MAT2A expression. Successful completion will define clearly the role of MAT proteins in liver metastasis.

项目 4：针对肝转移中的蛋氨酸腺苷转移酶抽象的该计划的一个关键中心假设是正常肝脏具有抑制转移的防御机制项目 4 的重点是甲硫氨酸腺苷转移酶 (MAT) 蛋白（其中 MAT1A）的作用。防御肝转移，而 MAT2A 和 MAT2B 则打破这种防御。形成甲基供体 S-腺苷甲硫氨酸 (SAMe) MAT1A 和 MAT2A 基因编码 MAT α1。分别是 α2 和 α2 催化亚基；第三个基因 MAT2B，编码调节 MAT2A- 的 β 亚基。 MAT1A 在正常肝脏中表达，在肝脏疾病中表达下调，而 MAT2A 和初步数据显示，MAT2B 在非肝组织中表达，在多种人类癌症中过度表达。 Mat1a 敲除 (KO) 小鼠对发生肝转移和释放细胞外细胞高度敏感含有癌蛋白的囊泡；而 MAT2A/MAT2B 与抑制转移的肿瘤抑制 miRNA miR-34a 和 miR-34b，但具有正前馈环与促转移癌基因 Forkhead box M1 (FOXM1) 相比，MAT1A 和 FOXM1 呈阴性。项目 4 检查了针对这些相互作用的三种分子抑制肝脏的作用。转移：SAMe；其代谢物甲硫腺苷（MTA）；以及FOXM1抑制剂FDI-6。假设癌细胞中高 MAT2A/2B 表达通过降低肝转移来增强肝转移 MAT1A，SAMe、MTA 和 FDI-6 部分通过靶向 MAT 蛋白抑制肝转移。患有转移性癌症的人类肝脏具有较低的 MAT1A 表达，GEO 数据库显示转移性癌症结肠癌、胰腺癌和前列腺癌具有较高的 MAT2A/2B 表达，Core B 将为人类提供。样本和动物模型来检查结肠、胰腺和肝脏转移中的这些 MAT 蛋白前列腺癌的三个具体目标：目标 1. 检查肝 MAT1A 表达在肝脏中的作用该目标将检验 MAT1A 的缺失会改变 MAT1A 释放的细胞外囊泡含量的假设。目的 2. 确定癌症表达的 MAT 蛋白是否有影响。该目标将阐明 MAT2A/MAT2B 介导的调节机制。 miR-34a/b 和 FOXM1，并检查癌细胞中较高的 MAT2A/2B 表达是否增强肝脏目标 3. 检查 SAMe、MTA 和 FDI-6 在肝脏中的机制和治疗潜力。该目标将评估这三种分子（单独和组合）对癌细胞的影响。体外迁移和侵袭将使用小鼠模型和原位在体内验证。使用肝转移患者的组织建立的患者来源的异种移植物具有协同作用。其中：项目 1，内皮糖蛋白/BMP 信号传导激活 FOXM1，项目 2，脂肪肝中 MAT1A 表达下降 Mat1a KO 肝脏具有更高的透明质酸；项目 3，因为 Metavert 降低了 MAT2A 表达。成功完成将明确 MAT 蛋白在肝转移中的作用。