YAP/TAZ与Notch信号通路调控肺癌的表型可塑性的分子机理及功能研究

肺癌具有明显的表型可塑性，不同亚型的肺癌可自发或在药物治疗时相互转分化。肺癌表型可塑性对肺癌患者的临床诊断分型与治疗造成干扰，是肿瘤细胞耐药性产生的重要原因。我们前期的研究发现，YAP/TAZ与Notch信号通路在调控小细胞肺癌的表型可塑性中发挥重要功能。YAP通过Notch信号通路依赖和非依赖的方式促使小细胞肺癌中的神经内分泌肿瘤细胞表型重塑转分化为非神经内分泌肿瘤细胞。然而，YAP/TAZ与Notch信号通路调控肺腺癌与小细胞肺癌之间表型重塑、互相转分化的分子机制尚不清晰。在本项目中，申请人将以小鼠EGFR突变驱动的肺腺癌以及小细胞肺癌动物模型为基础，构建研究肺癌表型可塑性的新模型、新系统，并结合转录组测序、表观遗传分析、肿瘤类器官等技术，系统研究YAP/TAZ与Notch信号通路调控肺癌表型可塑性的分子机制。该研究丰富和拓展肺癌表型可塑性的基础理论，也为肺癌的诊断与治疗提供新思路。

Lung cancer has great phenotypic plasticity, which manifests as the mutual transdifferentiation of different subtypes of lung cancers during tumorigenesis and drug treatment. Unlocking phenotypic plasticity of lung cancer has brought difficulties to the diagnosis and treatment of clinical lung cancer patients. Phenotypic remodeling of lung cancer is one of the key reasons for the drug resistance of tumor cells. In our previous work, we found that YAP/TAZ and Notch signaling pathways play an important role in unlocking phenotypic plasticity in small cell lung cancer. Activation of YAP induces neuroendocrine SCLC tumor cells to unlock phenotypic plasticity and transdifferentiate into non-neuroendocrine SCLC tumor cells through Notch-dependent and independent pathway. However, the functions and molecular mechanisms of YAP/TAZ and Notch pathways in regulating phenotypic plasticity and mutual transdifferentiation between lung adenocarcinoma and small cell lung cancer are still unclear. In this application, we plan to explore the molecular mechanisms how YAP/TAZ and Notch pathways regulate lung cancer phenotypic plasticity by using EGFR-driven lung adenocarcinoma and small cell lung cancer transgenic mouse models, in conjunction with transcriptome profiling, epigenetic and proteomic analysis, and tumor organoid. This work will provide novel insights into the basic theory of phenotypic plasticity of lung cancer, and diagnosis and treatment for lung cancer.