Mitotic polarization of transcription factors during asymmetric division establishes fate of forming cancer cells

作者：Liu Yongqing; Siles Laura; Lu Xiaoqin; Dean Kevin C; Cuatrecasas Miriam; Postigo Antonio^*; Dean Douglas C^*

来源：Nature Communications, 2018, 9(1): 2424.

DOI：10.1038/s41467-018-04663-1

A model of K-Ras-initiated lung cancer was used to follow the transition of precancerous adenoma to adenocarcinoma. In hypoxic, Tgf-beta 1-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-131 signaling that drives nuclear translocation of Yapl. 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.

• 出版日期2018-6-21