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 ChenXiaomin Wang, Tao Jiang, Jing Qu, Fuchou Tang, Guang Hui Liu

Research output: Contribution to journalArticle

51 Citations (Scopus)

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.

Original languageEnglish (US)
Article number10068
JournalNature communications
Volume6
DOIs
StatePublished - Dec 3 2015
Externally publishedYes

Fingerprint

phenotype
Neural Stem Cells
stem cells
Glioblastoma
Stem cells
Stem Cells
Phenotype
Carrier Proteins
Neoplasms
proteins
Tumors
tumors
Mitomycin
suppressors
Mesenchymal Stromal Cells
neoplasms
Transcriptome
Protein Binding
gene expression
apoptosis

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

PTEN deficiency reprogrammes human neural stem cells towards a glioblastoma stem cell-like phenotype. / Duan, Shunlei; Yuan, Guohong; Liu, Xiaomeng; Ren, Ruotong; Li, Jingyi; Zhang, Weizhou; Wu, Jun; Xu, Xiuling; Fu, Lina; Li, Ying; Yang, Jiping; Zhang, Weiqi; Bai, Ruijun; Yi, Fei; Suzuki, Keiichiro; Gao, Hua; Esteban, Concepcion Rodriguez; Zhang, Chuanbao; Belmonte, Juan Carlos Izpisua; Chen, Zhiguo; Wang, Xiaomin; Jiang, Tao; Qu, Jing; Tang, Fuchou; Liu, Guang Hui.

In: Nature communications, Vol. 6, 10068, 03.12.2015.

Research output: Contribution to journalArticle

Duan, S, Yuan, G, Liu, X, Ren, R, Li, J, Zhang, W, Wu, J, Xu, X, Fu, L, Li, Y, Yang, J, Zhang, W, Bai, R, Yi, F, Suzuki, K, Gao, H, Esteban, CR, Zhang, C, Belmonte, JCI, Chen, Z, Wang, X, Jiang, T, Qu, J, Tang, F & Liu, GH 2015, 'PTEN deficiency reprogrammes human neural stem cells towards a glioblastoma stem cell-like phenotype', Nature communications, vol. 6, 10068. https://doi.org/10.1038/ncomms10068
Duan, Shunlei ; Yuan, Guohong ; Liu, Xiaomeng ; Ren, Ruotong ; Li, Jingyi ; Zhang, Weizhou ; Wu, Jun ; Xu, Xiuling ; Fu, Lina ; Li, Ying ; Yang, Jiping ; Zhang, Weiqi ; Bai, Ruijun ; Yi, Fei ; Suzuki, Keiichiro ; Gao, Hua ; Esteban, Concepcion Rodriguez ; Zhang, Chuanbao ; Belmonte, Juan Carlos Izpisua ; Chen, Zhiguo ; Wang, Xiaomin ; Jiang, Tao ; Qu, Jing ; Tang, Fuchou ; Liu, Guang Hui. / PTEN deficiency reprogrammes human neural stem cells towards a glioblastoma stem cell-like phenotype. In: Nature communications. 2015 ; Vol. 6.
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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.",
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AU - Yuan, Guohong

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AU - Li, Jingyi

AU - Zhang, Weizhou

AU - Wu, Jun

AU - Xu, Xiuling

AU - Fu, Lina

AU - Li, Ying

AU - Yang, Jiping

AU - Zhang, Weiqi

AU - Bai, Ruijun

AU - Yi, Fei

AU - Suzuki, Keiichiro

AU - Gao, Hua

AU - Esteban, Concepcion Rodriguez

AU - Zhang, Chuanbao

AU - Belmonte, Juan Carlos Izpisua

AU - Chen, Zhiguo

AU - Wang, Xiaomin

AU - Jiang, Tao

AU - Qu, Jing

AU - Tang, Fuchou

AU - Liu, Guang Hui

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