The role of PCDH7 in lung cancer pathogenesis

PCDH7在肺癌发病机制中的作用

• 批准号: 9904349
• 负责人: Kathryn Ann O'Donnell
• 金额: $ 5.31万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9904349
• 关键词: Cancer Etiology; Cancer Patient; Cell Surface Proteins; Cell Surface Receptors; Cells; Cessation of life; Clinical; Complex; Data; Development; Effectiveness; Epidermal Growth Factor Receptor; Epithelial Cells; Family member; Genes; Genetic screening method; Human; In Vitro; KRAS2 gene; MAP Kinase Gene; MEKs; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Molecular; Mus; Mutagenesis; Non-Small-Cell Lung Carcinoma; Oncogenic; Pathogenesis; Protein Phosphatase 2A Regulatory Subunit PR53; Proteins; Role; Signal Pathway; Signal Transduction; Testing; Transgenic Mice; cancer cell; in vivo; inhibitor/antagonist; innovation; insight; lung tumorigenesis; mouse model; mutant; novel; overexpression; somatic cell gene editing; targeted treatment; therapeutic target; tumor; tumorigenesis

PROJECT SUMMARY Non-small cell lung cancer (NSCLC) is the most common form of lung cancer and is the leading cause of cancer-associated deaths worldwide. Given the limited effectiveness of current treatment regimes, there is a critical need for the development of new and innovative approaches to identify actionable therapeutic targets to treat NSCLC. We identified PROTOCADHERIN 7 (PCDH7) in a transposon mutagenesis screen for genes that promote transformation of human bronchial epithelial cells (HBECs). Indeed, Protocadherin family members represent an emerging class of molecules with important functions in cancer. We found that that PCDH7 is frequently overexpressed in lung cancer and that high expression of PCDH7 protein in human tumors strongly associates with poor survival of NSCLC patients. Our data demonstrate that PCDH7 overexpression potently enhances KRAS- and EGFR-induced MAPK signaling and tumorigenesis. Loss of PCDH7 sensitizes KRAS-mutant NSCLC cells to MEK inhibitors in vitro, and inhibits tumorigenesis in vivo. The overall objectives of this application are to define the oncogenic activity of PCDH7 in NSCLC using mouse models and human cells, evaluate PCDH7 as a therapeutic target, and identify the molecular mechanisms through which this cell surface protein promotes lung tumorigenesis. We propose to elucidate the role of this putative lung cancer driver gene by testing the following central hypothesis: PCDH7 promotes KRAS-and EGFR-driven lung tumorigenesis by forming a SET/PP2A inhibitory complex that potentiates MAPK- ERK signaling. Three Specific Aims will be pursued in order to test this hypothesis: In Aim 1, we will characterize the extent to which PCDH7 accelerates mutant KRAS- and EGFR-mediated tumorigenesis using a conditional PCDH7 transgenic mouse model, and inhibit PCDH7 using somatic genome editing in KrasLSL- G12D; Tp53 fl/fl mice. In Aim 2, we will elucidate the roles of SET and PP2A in PCDH7-induced MAPK signaling and tumorigenesis. Finally, in Aim 3, we will examine the extent to which PCDH7 inhibition enhances sensitivity to clinically approved inhibitors in NSCLC cells in vitro and in autochthonous mouse models. These aims will take advantage of our expertise, and that of our collaborators, to evaluate PCDH7 as a therapeutic target, and identify the mechanisms through which this cell surface protein promotes lung tumorigenesis. We anticipate that these studies will yield novel insights into the mechanisms of lung cancer pathogenesis and provide new opportunities to pursue this cell surface receptor as a therapeutic target in KRAS- and EGFR- driven lung cancers.

项目摘要 非小细胞肺癌（NSCLC）是肺癌最常见的形式，是 全球与癌症相关的死亡。考虑到当前治疗方案的有效性有限，有一个 开发新的和创新方法的批判性需要，以确定可行的治疗靶标 治疗NSCLC。我们在基因的转座子诱变筛选中鉴定了原钙粘蛋白7（PCDH7） 促进人支气管上皮细胞（HBEC）的转化。确实，原钙粘蛋白家族 成员代表具有癌症重要功能的新兴分子。我们发现 PCDH7经常在肺癌中过表达，并且在人类中PCDH7蛋白的高表达 肿瘤与NSCLC患者的存活率较差密切相关。我们的数据表明PCDH7 过表达可有效增强KRAS和EGFR诱导的MAPK信号传导和肿瘤发生。损失 PCDH7在体外将KRAS突变的NSCLC细胞敏感到MEK抑制剂，并抑制体内肿瘤发生。这 该应用程序的总体目标是使用鼠标定义NSCLC中PCDH7的致癌活性 模型和人类细胞，将PCDH7评估为治疗靶标，并确定分子机制 该细胞表面蛋白促进肺肿瘤发生。我们建议阐明这一点的作用 假定的肺癌驱动基因通过测试以下中心假设：PCDH7促进KRAS和 EGFR驱动的肺肿瘤发生通过形成set/pp2a抑制性复合物，以增强mapk- ERK信号。为了检验这一假设，将追求三个具体目标：在AIM 1中，我们将 表征PCDH7在多大程度上加速使用突变体KRAS和EGFR介导的肿瘤发生的程度 有条件的PCDH7转基因小鼠模型，并使用KRASLSL-中的体细胞基因组编辑抑制PCDH7 g12d; TP53 FL/FL小鼠。在AIM 2中，我们将阐明SET和PP2A在PCDH7诱导的MAPK信号传导中的作用 和肿瘤发生。最后，在AIM 3中，我们将研究PCDH7抑制的程度 对NSCLC细胞中临床认可的抑制剂的敏感性在体外和自围小鼠模型中的敏感性。这些 目标将利用我们的专业知识和我们的合作者的优势，以评估PCDH7作为治疗 靶标，并确定该细胞表面蛋白促进肺肿瘤发生的机制。我们 预计这些研究将产生对肺癌发病机理机制和 提供新的机会，将这种细胞表面受体作为KRAS和EGFR-的治疗靶点。 驱动的肺癌。