Organoids Model Transcriptional Hallmarks of Oncogenic KRAS Activation in Lung Epithelial Progenitor Cells.
Organoids Model Transcriptional Hallmarks of Oncogenic KRAS Activation in Lung Epithelial Progenitor Cells.
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DOI：
10.1016/j.stem.2020.07.022
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发表时间：
2020-10-01
期刊：
影响因子：
23.9
通讯作者：
Kim CF
中科院分区：
文献类型：
--
作者：
Dost AFM;Moye AL;Vedaie M;Tran LM;Fung E;Heinze D;Villacorta-Martin C;Huang J;Hekman R;Kwan JH;Blum BC;Louie SM;Rowbotham SP;Sainz de Aja J;Piper ME;Bhetariya PJ;Bronson RT;Emili A;Mostoslavsky G;Fishbein GA;Wallace WD;Krysan K;Dubinett SM;Yanagawa J;Kotton DN;Kim CF
突变型KRAS是上皮癌中常见的驱动因素。然而，上皮细胞中致癌KRAS激活后早期发生的分子变化仍知之甚少。我们在四组样本中比较了KRAS激活后单细胞分辨率下的转录变化。除了患者样本和基因工程小鼠模型外，我们还从原代小鼠和人诱导多能干细胞衍生的肺上皮细胞开发了类器官系统，以模拟早期肺腺癌。在所有四种情况下，表达致癌KRAS的肺泡上皮祖细胞（AT2）成熟谱系特征基因的表达降低。这些发现证明了我们的体外类器官方法在揭示致癌KRAS表达的早期后果方面的实用性。该资源提供了大量数据集，并描述了类器官工具，用于研究区分正常上皮祖细胞和早期肺癌的转录和蛋白质组变化，有助于寻找KRAS驱动肿瘤的靶点。
早期肺癌了解甚少。在此，作者引入了新的类器官系统来模拟肺癌。在小鼠和类器官模型以及IA期癌症中，表达KRAS的肺泡祖细胞谱系基因表达降低。这是关于早期肺癌分化缺失的首次报道。
Mutant KRAS is a common driver in epithelial cancers. Nevertheless, molecular changes occurring early after activation of oncogenic KRAS in epithelial cells remain poorly understood. We compared transcriptional changes at single cell resolution after KRAS activation in four sample sets. In addition to patient samples and genetically engineered mouse models, we developed organoid systems from primary mouse and human induced pluripotent stem cell derived lung epithelial cells to model early-stage lung adenocarcinoma. In all four settings, alveolar epithelial progenitor (AT2) cells expressing oncogenic KRAS had reduced expression of mature lineage identity genes. These findings demonstrate the utility of our in vitro organoid approaches for uncovering the early consequences of oncogenic KRAS expression. This resource provides an extensive collection of data sets and describes organoid tools to study the transcriptional and proteomic changes that distinguish normal epithelial progenitor cells from early-stage lung cancer, facilitating the search for targets for KRAS-driven tumors. Early-stage lung cancer is poorly understood. Here, the authors introduce new organoid systems to model lung cancer. KRAS-expressing alveolar progenitor cells had reduced expression of lineage genes in mouse and organoid models and stage IA cancers. This is the first report of loss of differentiation in early-stage lung cancer.
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