Identification of Active Bronchioalveolar Stem Cells as the Cell of Origin in Lung Adenocarcinoma
Identification of Active Bronchioalveolar Stem Cells as the Cell of Origin in Lung Adenocarcinoma
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DOI：
10.1158/0008-5472.can-21-2445
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发表时间：
2022-03-15
期刊：
影响因子：
11.2
通讯作者：
Deng, Jiong
中科院分区：
文献类型：
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作者：
Yin, Huijing;Jing, Bo;Deng, Jiong
虽然起始被确立为肿瘤发生的关键步骤，但肺腺癌起源细胞的身份和控制对起始敏感性的机制仍然难以捉摸。在这里，我们表明肺肿瘤抑制基因Gprc 5a敲除（KO）小鼠容易引发肺肿瘤发生。与野生型（WT）小鼠相比，Gprc 5a-KO小鼠肺中的支气管肺泡干细胞（BASC）和肺泡2型（AT 2）细胞异常扩增，表明Gprc 5a-KO可能通过增加小鼠肺中的起源细胞而赋予启动易感性。与来自WT小鼠（WT-BASC）的BASC相比，来自Gprc 5a-KO小鼠（KO-BASC）的BASC表现出显著增加的干性和自我更新潜力以及降低的分化能力。无论Gprc 5a状态如何，AT 2细胞都不具有自我更新潜力。与WT-BASCs相比，KO-BASCs表达干细胞样基因谱，具有上调的Abcg 2、EGFR和NF-κ B信号传导。阻断EGFR和NF-κ B信号传导抑制BASC和AT 2细胞的扩增和肺肿瘤发生。Abcg 2在活性KO-BASC以及肺肿瘤细胞中表达，但在静止期WT-BASC或AT 2细胞中不表达，支持肺腺癌细胞来源于Abcg 2阳性KO-BASC（活性）。总之，Gprc 5a缺失通过EGFR和NF-κ B信号转导失调导致活性BASC的扩增，这赋予了对肺肿瘤发生起始的易感性，标记Abcg 2-阳性BASCs可作为肺腺癌的候选细胞来源。意义活性支气管肺泡干细胞作为肺腺癌细胞来源的鉴定提供了对肺肿瘤发生机制的深入了解，并可促进有效策略的开发用于癌症预防和治疗。
While initiation is established as a critical step in tumorigenesis, the identity of the cell of origin for lung adenocarcinoma and the mechanism controlling susceptibility to initiation remain elusive. Here we show that lung tumor suppressor Gprc5a-knockout (KO) mice are susceptible to initiation of lung tumorigenesis. Bronchioalveolar stem cells (BASC) and alveolar type 2 (AT2) cells were aberrantly expanded in Gprc5a-KO mouse lungs compared with those in wild-type (WT) mice, suggesting that Gprc5a-KO might confer susceptibility to initiation by increasing the cell of origin in mouse lungs. BASCs from Gprc5a-KO mice (KO-BASC) exhibited significantly increased stemness and self-renewal potential and reduced differentiation capacity compared with BASCs from WT mice (WT-BASC). AT2 cells did not possess self-renewal potential regardless of Gprc5a status. KO-BASCs expressed a stem-like gene profile with upregulated Abcg2, EGFR, and NF-kappa B signaling compared with WT-BASCs. Blockade of EGFR and NF-kappa B signaling inhibited both expansion of BASC and AT2 cells and lung tumorigenesis. Abcg2 was expressed in active KO-BASCs as well as in lung tumor cells but not in quiescent WT-BASCs or AT2 cells, supporting that lung adenocarcinoma cells are derived from Abcg2-positive KO-BASCs (active). Taken together, Gprc5a deletion leads to expansion of active BASCs via dysregulated EGFR and NF-kappa B signaling that confers susceptibility to initiation of lung tumorigenesis, marking Abcg2-positive BASCs as candidate cell of origin for lung adenocarcinoma.Significance Identification of active bronchioalveolar stem cells as lung adenocarcinoma cells of origin provides insights into mechanisms of lung tumorigenesis and could facilitate development of effective strategies for cancer prevention and therapy.