Msi2 regulates the aggressiveness of Non-Small Cell Lung Cancer (NSCLC)

Msi2 调节非小细胞肺癌 (NSCLC) 的侵袭性

• 批准号: 9264497
• 负责人: ERICA A. GOLEMIS
• 金额: $ 23.29万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-19 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9264497
• 关键词: Ablation; Address; Adenocarcinoma; Adenoviruses; Alleles; Antineoplastic Agents; Basement membrane; Biological Process; Cancer Etiology; Cancer Patient; Cancer cell line; Cause of Death; Cell Line; Cells; Cessation of life; Clinical; Clinical Data; Clinical Trials; Complement; Cytotoxic agent; Data; Development; Down-Regulation; Drug Targeting; Drug resistance; E-Cadherin; Epithelial; Epithelium; Evaluation; Fibronectins; Future; Genes; Genetic Translation; Goals; Growth; Human; In Vitro; Infection; Intercellular Junctions; Invaded; Investigation; LoxP-flanked allele; Lung; Malignant neoplasm of lung; Mesenchymal; Messenger RNA; Modeling; Mouse Cell Line; Mus; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Numbness; Oncogenic; Pathway Analysis; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Phosphotransferases; Physicians; Physiological; Pre-Clinical Model; Prevention; Protein Array; Protein Array Analysis; Proteins; RNA-Binding Proteins; Regulation; Research Personnel; Role; Scientist; Signal Pathway; Signal Transduction; Solid Neoplasm; Source; Specimen; Structure of parenchyma of lung; TP53 gene; Testing; Therapeutic; Tight Junctions; Tissue Microarray; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Tumor Cell Invasion; Up-Regulation; Work; Xenograft procedure; cancer cell; cell motility; chemotherapeutic agent; docetaxel; epithelial to mesenchymal transition; experimental study; gamma secretase; improved; in vivo; in vivo Model; individualized medicine; inhibitor/antagonist; insight; kinase inhibitor; knock-down; leukemia; loss of function; lung tumorigenesis; mouse model; notch protein; novel; overexpression; phase II trial; preclinical study; protein E; public health relevance; response; screening; stem cell population; treatment response; treatment strategy; tumor; tumor growth; tumor progression

 DESCRIPTION (provided by applicant): Using the KrasLA1/+; P53R172H∆G/+ (KP) mouse model, which simulates NSCLC, we compared cell lines derived from non-metastatic versus highly metastatic tumors. This identified upregulation of Msi2, an RNA-binding protein that regulates mRNA translation, as one of the most consistent features of metastatic cells. In an initial probe of 123 primary human NSCLC specimens, it has been found that Msi2 is significantly elevated in tumors versus normal lung epithelium, suggesting relevance to NSCLC in patients. Msi2 knockdown in four independent murine and human metastatic NSCLC cell lines decreased invasion in vitro, with preliminary confirmation of reduced metastasis in vivo. Candidate pathway analysis and reverse-phase protein array (RPPA) screening identified EMT-associated proteins including the TGF-β receptor Type I (TGF-βRI), the Notch inhibitor Numb, fibronectin (FN1), and claudin-7, as strongly regulated by Msi2. The investigators hypothesize that Msi2 regulation of these proteins is critical for its role in invasion and metastasis, and provides essential support for Notch- and TGF-βRI dependent oncogenic signaling in a subset of metastatic NSCLC. The objective is to explore these mechanisms in vitro, determine whether Msi2 expression regulates the response to drugs targeting Notch and TGF-βRI, and determine whether the relationships we have identified predict pathway activity in human tumors. Aim 1 will validate functional significance of Msi2 dependent signaling effectors, focusing on interconnection between NUMB/Notch, TGF-β, and novel targets such as the cell junction regulator claudin-7. This work will emphasize the role of Msi2 expression on response to γ- secretase (Notch-targeting) and TGF-βRI inhibitors, and will combine in vitro analysis of signaling and drug response with xenograft analysis. Aim 2 will establish if expression of Msi2 expression correlates with Notch, TGF-β, CLDN7, and E-cadherin, and clinical data in cancer patients. In complementary experiments, the researchers will use a conditional 129S/Sv-Krastm3Tyj/J; Trp53tm1Brn/J; Msi2-/- mouse model to determine the action of Msi2 at discrete stages of lung tumorigenesis, including early growth, invasion, and metastasis.

 描述（由申请方提供）：使用模拟NSCLC的KrasLA 1/+; P53 R172 H β G/+（KP）小鼠模型，我们比较了来自非转移性肿瘤与高转移性肿瘤的细胞系。这确定了Msi 2（一种调节mRNA翻译的RNA结合蛋白）的上调是转移性细胞最一致的特征之一。在123个原发性人NSCLC标本的初始探针中，已经发现Msi 2在肿瘤中相对于正常肺上皮显著升高，表明与患者中的NSCLC相关。在四个独立的鼠和人转移性NSCLC细胞系中Msi 2敲低降低了体外侵袭，初步证实了体内转移减少。候选途径分析和反相蛋白阵列（RPPA）筛选鉴定了EMT相关蛋白，包括I型TGF-β受体（TGF-βRI）、Notch抑制剂Numb、纤连蛋白（FN 1）和紧密连接蛋白-7，这些蛋白受Msi 2强烈调控。研究人员假设，Msi 2对这些蛋白的调节对于其在侵袭和转移中的作用至关重要，并为转移性NSCLC亚组中Notch和TGF-βRI依赖性致癌信号传导提供了必要的支持。目的是在体外探索这些机制，确定Msi 2表达是否调节对靶向Notch和TGF-βRI的药物的反应，并确定我们已经确定的关系是否预测人类肿瘤中的通路活性。目的1将验证Msi 2依赖性信号传导效应物的功能意义，重点关注NUMB/Notch，TGF-β和新靶点（如细胞连接调节剂claudin-7）之间的相互作用。这项工作将强调Msi 2表达对γ-分泌酶（Notch靶向）和TGF-βRI抑制剂的反应的作用，并将联合收割机体外信号和药物反应分析与异种移植物分析相结合。目的2将确定Msi 2表达的表达是否与Notch、TGF-β、CLDN 7和E-钙粘蛋白以及癌症患者的临床数据相关。在补充实验中，研究人员将使用条件性129 S/Sv-Krastm 3 Tyj/J; Trp 53 tm 1Brn/J; Msi 2-/-小鼠模型来确定Msi 2在肺肿瘤发生的离散阶段的作用，包括早期生长，侵袭和转移。