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

• 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
• 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

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：靶向蛋氨酸腺苷转移酶治疗肝转移 摘要 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 成长。项目4的重点是蛋氨酸腺苷转移酶(MAT)蛋白的作用，以及MAT1a 防止肝脏转移，而MAT2A和MAT2B则破坏了这一防御。MAT催化了 形成S-腺苷蛋氨酸(同)，甲基供体。MAT1a和MAT2a基因编码MATα1 和α2催化亚基；第三个基因MAT2B编码β亚基，调节MAT2a- 编码酶。在正常肝脏中表达的MAT1A在肝病中表达下调，而MAT2A和MAT2A在肝病中表达下调。 MAT2B在非肝组织中表达，在多种人类肿瘤中高表达。初步数据显示 Mat1a基因敲除(KO)小鼠高度致敏，发生肝转移并释放细胞外 含有癌蛋白的囊泡；而MAT2A/MAT2B具有相互抑制作用 抑制转移的肿瘤抑制因子miR-34a和miR-34b，但具有正前馈环 与促进转移癌基因Forkhead box M1(FOXM1)连接。相反，MAT1A和FOXM1为负 相互规范。项目4检查了针对这些相互作用的三种分子抑制肝脏的效果。 转移：相同；其代谢物甲硫腺苷(MTA)；以及FOXM1抑制剂fDi-6。此项目测试 癌细胞高表达MAT2A/2B通过降低肝转移促进肝转移的假说 MAT1A、MTA和fDi-6部分通过靶向MAT蛋白抑制肝转移。重要的是 患有转移性癌症的人肝脏MAT1A表达较低，GEO数据库显示为转移性 结肠癌、胰腺癌和前列腺癌的MAT2A/2B表达较高。核心B将为人类提供 用标本和动物模型检测这些MAT蛋白在来自结肠、胰腺和肝转移瘤中的表达 前列腺癌超过三个特定目标：目的1.检测肝脏MAT1A在肝脏中表达的作用 转移。这一目标将检验这样一个假设，即MAT1A的丢失改变了细胞外小泡释放的内容 促进肝脏的转移生长。目的2.确定MAT蛋白的表达是否受癌症的影响 肝脏转移。这一目的将阐明MAT2A/MAT2B介导的调控机制 MiR-34a/b和FOXM1的表达，并检测在癌细胞中更高的MAT2A/2B表达是否促进肝脏 转移。目的3.检测Same、MTA和fDi-6在肝脏中的作用机制和治疗潜力 转移。这一目标将评估这三种分子(单独和联合)对癌细胞的影响。 体外迁移和侵袭。最好的治疗方法将在体内通过小鼠模型和原位实验进行验证。 使用肝转移患者的组织建立患者来源的异种移植。项目4协同增效 与：项目1，因为endoglin/BMP信号激活FOXM1，项目2，因为MAT1A在脂肪肝中表达下降 和Mat1a KO肝脏具有更高的透明质酸；以及项目3，因为美托维特降低了MAT2A的表达。 成功的完成将明确MAT蛋白在肝转移中的作用。