Roles of PTPN11 in regulating and driving epithelial cancer

PTPN11在调节和驱动上皮癌中的作用

基本信息

批准号：
8698356
负责人：
JIE WU
金额：
$ 33.91万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-08 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8698356
关键词：
Address Affect American Americas Animals Automobile Driving C-terminal Cancer Etiology Cancer Patient Carcinogens Carcinoma Cessation of life Communities Data Dependency Development Disease Enzymes Epidermal Growth Factor Receptor Epithelial Epithelial Cells Event GRB2 gene Goals Human Human Activities Intervention KRAS2 gene Knowledge Life Lung Lung Adenocarcinoma Lung Neoplasms Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Measures Mediating Medical Mutation Oncogenes Oncogenic PTPN11 gene Pathway interactions Phosphorylation Phosphotyrosine Play Preventive Preventive Intervention Property Protein Tyrosine Kinase Protein Tyrosine Phosphatase Proteomics Recruitment Activity Research Resources Role Signal Transduction Smoker Solid Neoplasm Testing Therapeutic Intervention Transgenic Mice Tumor Suppressor Proteins Tyrosine Phosphorylation cigarette smoking human disease improved in vivo insight lung Carcinoma lung xenograft mouse model mutant never smoker non-smoker novel prevent public health relevance recombinase research study tool tumor tumor growth tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Lung cancer is a major disease with unmet medical need. Identification of molecules that play critical roles in regulating lung malignant pathways is essential for improving the preventive and therapeutic interventions of this fatal disease. The goal of this study is to investigate the roles of PTPN11 (SHP2) in epithelial tumors focusing on lung adenocarcinoma. Mutant EGFR is a major lung adenocarcinoma driver oncogene found in never-smokers. Using novel transgenic mice, we will investigate in Specific Aim 1 whether SHP2 is essential for EGFR mutant-driven lung tumor and study mechanisms by which SHP2 mediates EGFR signaling and lung tumor development. Mutant KRAS is a major lung adenocarcinoma driver oncogene associated with heavy smokers. In Specific Aim 2, we will evaluate the SHP2 dependency of KRAS mutant lung adenocarcinoma and whether SHP2 inhibition prevents cigarette smoke carcinogen-induced lung tumors in transgenic mice. Animal lung and xenograft tumors will be analyzed by quantitative phosphoproteomics to gain insights into the mechanisms of SHP2 dependency of mutant EGFR and KRAS lung carcinoma in vivo. Previous studies of driver oncogenes have been focused on protein tyrosine kinases, while protein tyrosine phosphatases were perceived mostly as tumor suppressors. Consequently, there is near complete lack of knowledge about protein tyrosine phosphatase driver oncogenes in lung adenocarcinoma. PTPN11 mutations occur in lung adenocarcinoma and prostate cancer among other solid tumors. However, it is unclear whether these are passenger mutations or driver oncogene mutations in carcinoma and what properties confer a PTPN11 mutation the oncogenic activity in epithelial cells. In Specific Aim 3, we will analyze oncogenic activities of several PTPN11 mutations in lung epithelial cells to gain insights into the oncogenic activity of PTPN11 mutations in lung cancer. Taken together, this study could reveal important roles of a protein tyrosine phosphatase in two major lung cancer driver oncogene-associated lung adenocarcinoma. It will give novel insights into signaling events critical to both non-smoker and smoker-associated lung adenocarcinoma. In addition to the potential translational significance, by demonstrating the first protein tyrosine phosphatase driver oncogene in epithelial tumors and revealing the SHP2 dependency of KRAS mutant lung adenocarcinoma, the study could have significant conceptual impact in the field. Moreover, the novel Cre recombinase-mediated cassette exchange-enable transgenic mice characterized in this study will give the research community an important resource to accelerate mouse model studies of human diseases.

描述（由申请人提供）：肺癌是一种主要疾病，有未满足的医疗需求。鉴定在调节肺恶性途径中起关键作用的分子是改善这种致命疾病的预防和治疗干预措施至关重要。这项研究的目的是研究PTPN11（SHP2）在关注肺腺癌的上皮肿瘤中的作用。突变EGFR是在永不吸烟者中发现的主要肺腺癌驱动癌。使用新型的转基因小鼠，我们将在特定的目标1中研究SHP2是否对于EGFR突变驱动的肺肿瘤和研究机制是否至关重要，SHP2介导EGFR信号传导和肺部肿瘤的发展。突变的KRAS是与吸烟者相关的主要肺腺癌驱动器癌基因。在特定目标2中，我们将评估KRAS突变肺腺癌的SHP2依赖性以及SHP2抑制是否阻止了转基因小鼠中烟癌诱发的烟癌诱导的肺肿瘤。动物肺和异种移植肿瘤将通过定量磷酸蛋白质组学进行分析，以洞悉体内突变体EGFR和KRAS肺癌SHP2依赖性的机制。先前对驱动癌基因的研究集中在蛋白质酪氨酸激酶上，而蛋白质酪氨酸磷酸酶主要被视为肿瘤抑制剂。因此，几乎完全缺乏关于肺腺癌中蛋白质酪氨酸磷酸酶驱动的癌基因的知识。 PTPN11突变发生在其他实体瘤中的肺腺癌和前列腺癌。但是，目前尚不清楚这些是癌中的乘客突变还是驱动癌基因突变，以及哪些特性赋予PTPN11突变的上皮细胞中的致癌活性。在特定的目标3中，我们将分析肺上皮细胞中几种PTPN11突变的致癌活性，以洞悉肺癌中PTPN11突变的致癌活性。综上所述，这项研究可以揭示蛋白质酪氨酸磷酸酶在两个主要的肺癌驱动癌基因相关的肺腺癌中的重要作用。它将为对非吸烟者和与吸烟者相关的肺腺癌至关重要的信号事件提供新的见解。除了潜在的翻译显着性外，通过证明上皮肿瘤中的第一个蛋白酪氨酸磷酸酶驱动癌基因并揭示了KRAS KRAS突变体肺腺癌的SHP2依赖性，该研究可能在该领域具有重大概念影响。此外，这项研究中特征的新型CRE重组酶介导的盒式盒式交换 - 可启用的转基因小鼠将为研究界提供一个重要的资源，以加速小鼠模型的人类疾病研究。