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（由申请人提供）：使用模拟 NSCLC 的 KrasLA1/+；P53R172HΔG/+ (KP) 小鼠模型，我们比较了来自非转移性肿瘤和高度转移性肿瘤的细胞系，这确定了 Msi2（一种 RNA）的上调。调节 mRNA 翻译的结合蛋白是转移细胞最一致的特征之一，在对 123 个原发性人类 NSCLC 样本的初步探测中，它已被证实。研究人员发现，与正常肺上皮细胞相比，Msi2 在肿瘤中显着升高，这表明在四种独立的小鼠和人类转移性 NSCLC 细胞系体外侵袭中，Msi2 敲低与患者的相关性降低，并初步证实了体内转移减少。反相蛋白阵列 (RPPA) 筛选鉴定出 EMT 相关蛋白，包括 I 型 TGF-β 受体 (TGF-βRI)、Notch 抑制剂 Numb、纤连蛋白 (FN1)、和claudin-7，受到Msi2的强烈调节。研究人员发现，Msi2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，并为转移性非小细胞肺癌中依赖Notch和TGF-βRI的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 Msi2 表达是否调节对靶向 Notch 和 TGF-βRI 的药物的反应，并确定我们已确定的关系是否可以预测人类肿瘤中的通路活性。 1 将验证 Msi2 依赖性信号传导效应器的功能意义，重点关注 NUMB/Notch、TGF-β 和细胞连接调节因子claudin-7 等新靶标之间的互连。这项工作将强调 Msi2 表达对 γ- 反应的作用。目标 2 将确定 Msi2 表达是否与相关性相关。 Notch、TGF-β、CLDN7 和 E-钙粘蛋白以及癌症患者的临床数据，研究人员将使用条件 129S/Sv-Krastm3Tyj/J；Trp53tm1Brn/J； Msi2 在肺肿瘤发生的不同阶段（包括早期生长、侵袭和转移）的作用。