肺癌进化历经基因突变、分子表达异常、非典型增生、原位癌、微浸润癌及浸润癌的多阶段发展过程。研究发现一些关键信号通路在小鼠早期肺腺瘤进化为肺腺癌的过程中被激活，但是目前仍缺乏对肺癌进化的系统性研究。基于近期国内外研究进展和我们前期研究结果，我们提出假设：在肺癌的早期进化过程中，由于关键分子靶点及调控位点出现异常，导致肺癌进化发展，而发现这些特异性靶点,将对肺癌早期精准诊断及干预有着重要的意义。本课题将建立肺癌进化患者队列，拟采用单细胞测序技术，通过对不同病理阶段肺癌组织的细胞核进行scRNA-seq和scATAC-seq测序，寻找肺癌进化的关键驱动基因、及特异性开放调控区域与基因表达的关联，揭示不同阶段肿瘤细胞亚群的分子特征变化。结合生物信息分析，描绘肺癌进化的分子图谱，发现肺癌进化过程关键的分子靶点，探寻阻断肺癌由早期向晚期进展的有效方法，为肺癌的早期精准干预提供科学依据。

The evolution of lung cancer underwent multistage of gene mutation, abnormal molecular expression, atypical adenomatous hyperplasia, adenocarcinoma in situ, minimally invasive adenocarcinoma and invasive adenocarcinoma. It has been found that some important signaling pathways play an important role in the progression of lung adenoma to lung adenocarcinoma, while there was still lack of comprehensive study on the evolution of lung cancer. Based on the recent research progress and the results of our previous studies, we propose the hypotheses that some key molecular targets and signaling pathways activated when lung cancer evolving from benign to malignant, so find the key epigenetic targets will be significant to the precise diagnosis and intervention of lung cancer. This study will establish lung cancer patient cohort with different evolution stage, and base on single cell RNA-seq and single cell ATAC-seq performed on the nuclei of different pathological types of patients, we could find the key driver gene of lung cancer evolution, the relationship between the specific regulatory regions and gene expression, then reveal the molecular characteristics of cell subgroups at different stages. Combined with bioinformatic analysis, we would map the molecular profiling, and discover all cellular subpopulations and key molecular targets in the evolution of lung cancer. The results could explore a new way to blocking the cancer progress, and provide a scientific basis for precise intervention of lung cancer.