title: PTEN deficiency reprogrammes human neural stem cells towards a glioblastoma stem cell-like phenotype.
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.
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Shunlei
authors.initials: S
authors.lastname: Duan
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Guohong
authors.initials: G
authors.lastname: Yuan
authors.affiliation: Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Xiaomeng
authors.initials: X
authors.lastname: Liu
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.|FSU-CAS Innovation Institute, Foshan 528000, China.|State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Ruotong
authors.initials: R
authors.lastname: Ren
authors.affiliation: Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Jingyi
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Weizhou
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Jun
authors.identifier: http://orcid.org/0000-0001-9863-1668
authors.initials: J
authors.lastname: Wu
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Xiuling
authors.initials: X
authors.lastname: Xu
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Fu
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Jiping
authors.initials: J
authors.lastname: Yang
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Weiqi
authors.initials: W
authors.lastname: Zhang
authors.affiliation: FSU-CAS Innovation Institute, Foshan 528000, China.|State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Ruijun
authors.initials: R
authors.lastname: Bai
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Yi
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.|Universidad Católica San Antonio de Murcia (UCAM) Campus de los Jerónimos, No 135 Guadalupe, 30107 Murcia, Spain.
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Research Center for Translational Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Gao
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Concepcion Rodriguez
authors.initials: CR
authors.lastname: Esteban
authors.affiliation: Beijing Institute for Brain Disorders, Beijing 100069, China.
authors.forename: Chuanbao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Izpisua Belmonte
authors.affiliation: Cell Therapy Center, Xuanwu Hospital Capital Medical University, Beijing 100053, China.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Beijing Institute for Brain Disorders, Beijing 100069, China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Beijing Institute for Brain Disorders, Beijing 100069, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Qu
authors.affiliation: Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing 100871, China.|Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing 100871, China.|Center for Molecular and Translational Medicine, CMTM, Beijing 100101, China.|Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Fuchou
authors.initials: F
authors.lastname: Tang
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.|FSU-CAS Innovation Institute, Foshan 528000, China.|Beijing Institute for Brain Disorders, Beijing 100069, China.|Center for Molecular and Translational Medicine, CMTM, Beijing 100101, China.
authors.forename: Guang-Hui
authors.identifier: http://orcid.org/0000-0001-9289-8177
authors.initials: GH
authors.lastname: Liu
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000201:enzymology*; D058953:Neural Stem Cells / Q000166:cytology / Q000201:enzymology*; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics; D010641:Phenotype
chemical_list: D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse