A model of K-Ras-initiated lung cancer was used to follow the transition of precancerous adenoma to adenocarcinoma. In hypoxic, Tgf-β1-rich interiors of adenomas, we show that adenoma cells divide asymmetrically to produce cancer-generating cells highlighted by epithelial mesenchymal transition and a CD44/Zeb1 loop. In these cells, Zeb1 represses the Smad inhibitor Zeb2/Sip1, causing Pten loss and launching Tgf-β1 signaling that drives nuclear translocation of Yap1. Surprisingly, the nuclear polarization of transcription factors during mitosis establishes parent and daughter fates prior to cytokinesis in sequential asymmetric divisions that generate cancer cells from precancerous lesions. Mutation or knockdown of Zeb1 in the lung blocked the production of CD44^hi, Zeb1^hi cancer-generating cells from adenoma cells. A CD44/Zeb1 loop then initiates two-step transition of precancerous cells to cancer cells via a stable intermediate population of cancer-generating cells. We show these initial cancer-generating cells are independent of cancer stem cells generated in tumors by p53-regulated reprogramming of existing cancer cells.

中文翻译：

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在不对称分裂过程中转录因子的有丝分裂极化确定了形成癌细胞的命运。

使用K-Ras引发的肺癌模型来追踪癌前腺瘤向腺癌的转变。在缺氧，富含Tgf-β1的腺瘤内部，我们显示出腺瘤细胞不对称分裂，产生上皮间充质转变和CD44 / Zeb1环突出显示的癌细胞。在这些细胞中，Zeb1抑制Smad抑制剂Zeb2 / Sip1，导致Pten丢失并启动Tgf-β1信号传导，从而驱动Yap1的核易位。出人意料的是，有丝分裂期间转录因子的核极化在胞质分裂之前以顺序的不对称分裂建立了父子命运，这是由癌前病变产生癌细胞的。肺中Zeb1的突变或敲低阻止了CD44 ^hi，Zeb1 ^hi的产生腺瘤细胞产生的癌细胞。然后，CD44 / Zeb1环通过稳定的癌症发生细胞中间种群启动癌前细胞向癌细胞的两步过渡。我们显示这些最初的致癌细胞独立于通过现有癌细胞的p53调控重编程在肿瘤中产生的癌症干细胞。