Cellular Origins of EGFR-driven Lung Cancer Cells Determines Sensitivity to Therapy

The purpose of this research is to study the cellular origins of EGFR-mutant lung cancers and their responses to therapies. We discovered that activation of EGFR T790M/L858R mutation in lung epithelial cells can drive lung cancers with alveolar or bronchiolar features, which can be originated from alveolar type 2 (AT2) cells or bronchioalveolar stem cells (BASCs), but not basal cells or club cells of the trachea. Crucially, the tumoroids with different cell-of-origins or epigenetic states had distinct drug vulnerabilities. RNA-sequencing profiles of murine lung organoids with or without EGFR T790M/L858R mutations before ex vivo transplantation, and EGFR T790M/L858R tumor organoids after ex vivo transplantation.

本研究旨在探究表皮生长因子受体（Epidermal Growth Factor Receptor, EGFR）突变型肺癌的细胞起源及其对治疗的应答反应。我们发现，在肺上皮细胞中激活EGFR T790M/L858R双突变，可驱动具有肺泡或细支气管特征的肺癌发生；此类肿瘤的起源细胞可为肺泡2型（Alveolar Type 2, AT2）细胞或细支气管肺泡干细胞（Bronchioalveolar Stem Cells, BASCs），而非气管的基底细胞或克拉拉细胞（club cells）。至关重要的是，具有不同细胞起源或表观遗传状态的肿瘤类器官，其药物敏感性存在显著差异。本数据集包含离体移植前携带或不携带EGFR T790M/L858R突变的小鼠肺类器官，以及离体移植后EGFR T790M/L858R突变型肿瘤类器官的RNA测序（RNA-sequencing）谱数据。