NOTCH信号通路在肺腺鳞癌的腺-鳞转分化中的作用及其机制研究

肺腺鳞癌的克隆起源和演化机制是影响临床诊疗策略制定的关键因素之一。不同于传统观点认为肺腺鳞癌是由腺癌和鳞癌成分组成的混合瘤，课题组近期基于中国人群基因组测序的研究结果提出了肺腺鳞癌发生的“腺癌单克隆起源”学说（Ann Oncol, 2020）。基于NOTCH和TP63信号通路在决定鳞癌细胞分化命运的重要性，结合前期发现肺腺鳞癌中存在NOTCH基因突变及其相关活化产物分子表达受抑，提出如下科学假说：肺腺癌NOTCH突变导致功能缺失，通过与TP63交互作用实现腺-鳞转分化，最终形成肺腺鳞癌。本项目将通过临床样本分析以及建立NOTCH特定位点突变的细胞模型和动物模型，明确NOTCH特定位点突变的功能及其在腺-鳞转分化中的作用，进一步探寻NOTCH-TP63通路相关作用机制。该研究将深入阐明腺-鳞转分化的分子机制，完善腺鳞癌发生的单克隆起源学说，为优化诊疗方案及确定有效治疗靶点提供科学依据。

The clonal origin and evolutional mechanism of lung adenosquamous carcinoma (ASC) dictate the major determinants in the decision-making related to diagnostic and treatment strategies. Apart from the traditional understanding that lung ASC merely contained a mixture of lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC), our recent findings demonstrated a monoclonal origin of lung ASC from ADC, based on the finding of gene mapping of lung ASC in Chinese population (Ann Oncol, 2020). On the basis of the critical role that NOTCH and TP63 played in the determination on the squamous differentiation fate of lung SCC and the fact that NOTCH mutation and down-regulation was frequently observed in lung ASC, a hypothesis was prompted that as a aftermath of NOTCH mutation, NOTCH malfunction together with the collaboration of TP63 would eventually result in the transdifferentiation from ADC to SCC via NOTCH-TP63 signal axis during the development of lung ASC. Therefore, we intend to identify functional characterization of specific NOTCH mutations and its role in the transdifferentiation from ADC to SCC in vitro and in vivo and to explore how NOTCH-TP63 axis is involved in the transdifferentiation from ADC to SCC. This study will further clarify the molecular mechanism of the transdifferentiation from ADC to SCC, better off the theory of monoclonal origin of lung ASC, and provide theoretical basis for the effective therapeutic target and diagnosis and treatment.