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

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, Hua Gao, Concepcion Rodriguez Esteban, Chuanbao Zhang, Juan Carlos Izpisua Belmonte, Zhiguo Chen, Xiaomin Wang, Tao Jiang, Jing Qu (), Fuchou Tang () and Guang-Hui Liu ()
Additional contact information
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
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
Fei Yi: Stanford University School of Medicine
Keiichiro Suzuki: Gene Expression Laboratory, Salk Institute for Biological Studies
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
Guang-Hui Liu: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms10068

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