肺癌是最难治愈的癌症之一，也是目前死亡病例和发病病例最多的癌症，对人类健康造成严重威胁。虽然现有各种小鼠肺癌模型加强了我们对于肺癌的发生、发展和治疗的认识，但由于物种差异等原因，这些模型还不能全面有效模拟肺癌病人的病理特征及疾病进程。对此，我们拟构建癌基因KRAS(G12D)基因敲入及抑癌基因TP53和PTEN诱导性敲除的人类胚胎干细胞（hESCs）细胞株，体外分化hESCs为肺类器官（organoid）并传代，体外研究KRAS(G12D)、TP53和PTEN对肺类器官中不同类型细胞的成瘤作用，移植肺类器官细胞至免疫缺陷小鼠肾包膜下及肺部，体内研究其成瘤性。hESCs具有无限增殖能力，可提供足够肺类器官重复性建立此体外/体内新型自发性肺癌模型。此模型一旦构建成功，将成为研究肺癌发生发展机制以及寻找新疗法的一种重要工具。

Lung cancer is the first leading cause of cancer death and the most commonly diagnosed cancer. Even worse, the overall 5-year survival rate is about 15%, and patients with lung cancer are of minimal chance to be cured. Over decades, mouse models of lung cancer have been widely used to investigate the mechanisms underlying tumor initiation and progression, as well as targeted therapies and drug resistance. However, these models show limited similarities with patients. The major reason accounting for the discrepancy is believed to be the inherent physiological differences between the two species. To overcome this limitation, we plan to establish novel cancer models based on human embryonic stem cells (hESCs) -derived organoids. We will create KRAS(G12D) knock-in and inducible TP53 and PTEN knock-out hESCs. These gene-edited hESCs will be differentiated into lung organoids in vitro, and the tumorigenesis potential of variant cell types in the organoids will be investigated. The lung organoids will be ectopically or orthotopically transplanted under kidney capsule or in the lung of immune-compromised NSG mice, and their tumorigenesis ability will be investigated in vivo. Since hESCs have two features, self-renewal and pluripotency, unlimited amount of lung organoids could be differentiated from gene-edited hESCs to make the organoid tumor model. The novel model will be a powerful system to study the molecular and cellular mechanisms underlying lung cancer initiation and progression, as well as be a platform to screen novel drugs to treat human lung cancer.