Roles of PTPN11 in regulating and driving epithelial cancer

描述（由申请人提供）：肺癌是一种医疗需求未得到满足的重大疾病。鉴定在调节肺恶性肿瘤途径中起关键作用的分子， 这对改善这一致命疾病的预防和治疗干预至关重要。本研究的目的是探讨PTPN11（SHP 2）在上皮性肿瘤中的作用，重点是肺腺癌。突变EGFR是在从不吸烟者中发现的主要肺腺癌驱动癌基因。使用新型转基因小鼠，我们将在特定目标1中研究SHP 2是否对EGFR突变驱动的肺肿瘤至关重要，并研究SHP 2介导EGFR信号传导和肺肿瘤发展的机制。突变型KRAS是与重度吸烟者相关的主要肺腺癌驱动癌基因。在具体目标2中，我们将评估KRAS突变型肺腺癌的SHP 2依赖性，以及SHP 2抑制是否能预防转基因小鼠中香烟烟雾致癌物诱导的肺肿瘤。将通过定量磷酸蛋白质组学分析动物肺和异种移植肿瘤，以深入了解突变型EGFR和KRAS肺癌体内的SHP 2依赖性机制。以往对驱动癌基因的研究主要集中在蛋白酪氨酸激酶上，而蛋白酪氨酸磷酸酶被认为是肿瘤抑制因子。因此，对肺腺癌中的蛋白酪氨酸磷酸酶驱动癌基因几乎完全缺乏了解。PTPN11突变发生在肺腺癌和前列腺癌以及其他实体瘤中。然而，目前还不清楚这些是乘客突变还是癌基因突变的驱动器，以及什么性质赋予PTPN11突变上皮细胞中的致癌活性。在具体目标3中，我们将分析肺上皮细胞中几种PTPN11突变的致癌活性，以深入了解PTPN11突变在肺癌中的致癌活性。总之，这项研究可以揭示蛋白酪氨酸磷酸酶在两种主要肺癌驱动癌基因相关肺腺癌中的重要作用。它将为非吸烟者和吸烟者相关肺腺癌的关键信号事件提供新的见解。除了潜在的翻译意义外，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KRAS突变肺腺癌的SHP 2依赖性，该研究可能在该领域产生重大的概念性影响。此外，本研究中表征的新型Cre重组酶介导的盒式交换使能转基因小鼠将为研究界提供重要资源，以加速人类疾病的小鼠模型研究。

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.