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

Author

Listed:
  • Yongqing Liu

    (University of Louisville Health Sciences Center
    University of Louisville Health Sciences Center
    University of Louisville Health Sciences Center)

  • Laura Siles

    (CIBERehd)

  • Xiaoqin Lu

    (University of Louisville Health Sciences Center)

  • Kevin C. Dean

    (University of Louisville Health Sciences Center)

  • Miriam Cuatrecasas

    (University of Barcelona
    IDIBAPS)

  • Antonio Postigo

    (University of Louisville Health Sciences Center
    CIBERehd
    ICREA)

  • Douglas C. Dean

    (University of Louisville Health Sciences Center
    University of Louisville Health Sciences Center
    University of Louisville Health Sciences Center)

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.

Suggested Citation

  • Yongqing Liu & Laura Siles & Xiaoqin Lu & Kevin C. Dean & Miriam Cuatrecasas & Antonio Postigo & Douglas C. Dean, 2018. "Mitotic polarization of transcription factors during asymmetric division establishes fate of forming cancer cells," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04663-1
    DOI: 10.1038/s41467-018-04663-1
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    Cited by:

    1. M. C. Martinez-Campanario & Marlies Cortés & Alazne Moreno-Lanceta & Lu Han & Chiara Ninfali & Verónica Domínguez & María J. Andrés-Manzano & Marta Farràs & Anna Esteve-Codina & Carlos Enrich & Franci, 2023. "Atherosclerotic plaque development in mice is enhanced by myeloid ZEB1 downregulation," Nature Communications, Nature, vol. 14(1), pages 1-21, December.

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