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PTEN deficiency reprogrammes human neural stem cells towards a glioblastoma stem cell-like phenotype

Author

Listed:
  • Shunlei Duan

    (National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences)

  • Guohong Yuan

    (National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences)

  • Xiaomeng Liu

    (Biodynamic Optical Imaging Center, College of Life Sciences, Peking University)

  • Ruotong Ren

    (National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
    FSU-CAS Innovation Institute
    State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences)

  • Jingyi Li

    (Biodynamic Optical Imaging Center, College of Life Sciences, Peking University)

  • Weizhou Zhang

    (Carver College of Medicine, University of Iowa)

  • Jun Wu

    (Gene Expression Laboratory, Salk Institute for Biological Studies)

  • Xiuling Xu

    (National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences)

  • Lina Fu

    (National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences)

  • Ying Li

    (National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences)

  • Jiping Yang

    (National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences)

  • Weiqi Zhang

    (National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences)

  • Ruijun Bai

    (FSU-CAS Innovation Institute
    State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences)

  • Fei Yi

    (Stanford University School of Medicine)

  • Keiichiro Suzuki

    (Gene Expression Laboratory, Salk Institute for Biological Studies
    Universidad Católica San Antonio de Murcia (UCAM) Campus de los Jerónimos)

  • Hua Gao

    (Research Center for Translational Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University)

  • Concepcion Rodriguez Esteban

    (Gene Expression Laboratory, Salk Institute for Biological Studies)

  • Chuanbao Zhang

    (Beijing Institute for Brain Disorders)

  • Juan Carlos Izpisua Belmonte

    (Gene Expression Laboratory, Salk Institute for Biological Studies)

  • Zhiguo Chen

    (Cell Therapy Center, Xuanwu Hospital Capital Medical University)

  • Xiaomin Wang

    (Beijing Institute for Brain Disorders)

  • Tao Jiang

    (Beijing Institute for Brain Disorders)

  • Jing Qu

    (State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences)

  • Fuchou Tang

    (Biodynamic Optical Imaging Center, College of Life Sciences, Peking University
    Ministry of Education Key Laboratory of Cell Proliferation and Differentiation
    Center for Molecular and Translational Medicine, CMTM
    Peking-Tsinghua Center for Life Sciences, Peking University)

  • Guang-Hui Liu

    (National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
    FSU-CAS Innovation Institute
    Beijing Institute for Brain Disorders
    Center for Molecular and Translational Medicine, CMTM)

Abstract

PTEN is a tumour suppressor frequently mutated in many types of cancers. Here we show that targeted disruption of PTEN leads to neoplastic transformation of human neural stem cells (NSCs), but not mesenchymal stem cells. PTEN-deficient NSCs display neoplasm-associated metabolic and gene expression profiles and generate intracranial tumours in immunodeficient mice. PTEN is localized to the nucleus in NSCs, binds to the PAX7 promoter through association with cAMP responsive element binding protein 1 (CREB)/CREB binding protein (CBP) and inhibits PAX7 transcription. PTEN deficiency leads to the upregulation of PAX7, which in turn promotes oncogenic transformation of NSCs and instates ‘aggressiveness’ in human glioblastoma stem cells. In a large clinical database, we find increased PAX7 levels in PTEN-deficient glioblastoma. Furthermore, we identify that mitomycin C selectively triggers apoptosis in NSCs with PTEN deficiency. Together, we uncover a potential mechanism of how PTEN safeguards NSCs, and establish a cellular platform to identify factors involved in NSC transformation, potentially permitting personalized treatment of glioblastoma.

Suggested Citation

  • Shunlei Duan & Guohong Yuan & Xiaomeng Liu & Ruotong Ren & Jingyi Li & Weizhou Zhang & Jun Wu & Xiuling Xu & Lina Fu & Ying Li & Jiping Yang & Weiqi Zhang & Ruijun Bai & Fei Yi & Keiichiro Suzuki & Hu, 2015. "PTEN deficiency reprogrammes human neural stem cells towards a glioblastoma stem cell-like phenotype," Nature Communications, Nature, vol. 6(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms10068
    DOI: 10.1038/ncomms10068
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