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

Yongqing Liu,Xiaoqin Lu,Laura Siles,Antonio Postigo,Douglas C Dean,Kevin C Dean,Miriam Cuatrecasas

doi:10.1038/s41467-018-04663-1

Abstract

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 CD44hi, Zeb1hi 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.

Highlights

A model of K-Ras-initiated lung cancer was used to follow the transition of precancerous adenoma to adenocarcinoma
cancer stem cells (CSC) display normal stem cell properties such as asymmetric division, there are key differences in pathways and gene expression patterns in CSC vs. stem cells. The foremost among these differences is tissue stems cells display an epithelial-like phenotype, and iduced pluripotent stem cells reprogramming to generate stem-like cells requires a mesenchymal-to-epithelial transition[4], whereas CSC are characterized by an opposing epithelial mesenchymal transition (EMT), which can be driven by induction of EMT transcription factors such as Zeb[12,5]
Mutation or knockdown of Zeb[1] in the lung blocked the production of these Zeb1hi, CD44hi cancer-generating cluster cells from adenoma cells, in turn inhibiting cancer cell formation. These results provide evidence that a CD44/Zeb[1] loop is activated in vivo at sites of hypoxia and Tgf-β1 accumulation in expanding precancerous adenomas, and this loop initiates a two-step pathway in which precancerous cells transition to cancer cells via a stable intermediate population of cancergenerating cells (CGC)

Summary

Introduction

A model of K-Ras-initiated lung cancer was used to follow the transition of precancerous adenoma to adenocarcinoma. The foremost among these differences is tissue stems cells display an epithelial-like phenotype, and iduced pluripotent stem cells (iPS) reprogramming to generate stem-like cells requires a mesenchymal-to-epithelial transition[4], whereas CSC are characterized by an opposing epithelial mesenchymal transition (EMT), which can be driven by induction of EMT transcription factors such as Zeb[12,5] This EMT in CSC is linked to high expression of CD44, which marks CSC in tumors including breast and lung cancers[6,7,8,9], and a positive CD44/Zeb[1] loop has been shown to drive EMT and reprogramming of existing cancer cells to a CSC phenotype[10,11]. As opposed to compound mutations generated simultaneously in mouse models, mutations are thought to arise sequentially over a long period in patients In this regard, it is of note that K-Ras mutation alone initiates a pathway leading to lung AC in mice, but with this single mutation, the process is highlighted by a protracted period of precancerous lesion expansion[12,20]. AC cells appear later in these adenomas, and they expand into large tumors that invade airways

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Conclusion