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Establishment of human iPSC-based models for the study and targeting of glioma initiating cells

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  • Ignacio Sancho-Martinez

    (Gene Expression Laboratory Belmonte, Salk Institute for Biological Studies
    Present address: Centre for Stem Cells and Regenerative Medicine, King’s College London, 28th Floor, Tower Wing, Guy’s Hospital, Great Maze Pond, London SE1 9RT, UK)

  • Emmanuel Nivet

    (Gene Expression Laboratory Belmonte, Salk Institute for Biological Studies
    Present address: Aix Marseille Université, CNRS, NICN UMR 7259, Marseille 13344, France)

  • Yun Xia

    (Gene Expression Laboratory Belmonte, Salk Institute for Biological Studies
    Present address: Lee Kong Chian School of Medicine, Experimental Medicine Building, 59 Nanyang Drive, Singapore 636921, Singapore)

  • Tomoaki Hishida

    (Gene Expression Laboratory Belmonte, Salk Institute for Biological Studies)

  • Aitor Aguirre

    (Gene Expression Laboratory Belmonte, Salk Institute for Biological Studies)

  • Alejandro Ocampo

    (Gene Expression Laboratory Belmonte, Salk Institute for Biological Studies)

  • Li Ma

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

  • Robert Morey

    (University of California, San Diego, Sanford Consortium for Regenerative Medicine)

  • Marie N. Krause

    (Gene Expression Laboratory Belmonte, Salk Institute for Biological Studies)

  • Andreas Zembrzycki

    (Molecular Neurobiology Laboratory, Salk Institute for Biological Studies)

  • Olaf Ansorge

    (West Wing, Level 1, John Radcliffe Hospital)

  • Eric Vazquez-Ferrer

    (Gene Expression Laboratory Belmonte, Salk Institute for Biological Studies)

  • Ilir Dubova

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

  • Pradeep Reddy

    (Gene Expression Laboratory Belmonte, Salk Institute for Biological Studies)

  • David Lam

    (Gene Expression Laboratory Belmonte, Salk Institute for Biological Studies)

  • Yuriko Hishida

    (Gene Expression Laboratory Belmonte, Salk Institute for Biological Studies)

  • Min-Zu Wu

    (Gene Expression Laboratory Belmonte, Salk Institute for Biological Studies)

  • Concepcion Rodriguez Esteban

    (Gene Expression Laboratory Belmonte, Salk Institute for Biological Studies)

  • Dennis O’Leary

    (Molecular Neurobiology Laboratory, Salk Institute for Biological Studies)

  • Geoffrey M. Wahl

    (Gene Expression Laboratory Wahl, Salk Institute for Biological Studies)

  • Inder M. Verma

    (Laboratory of Genetics, Salk Institute for Biological Studies)

  • Louise C. Laurent

    (University of California, San Diego, Sanford Consortium for Regenerative Medicine)

  • Juan Carlos Izpisua Belmonte

    (Gene Expression Laboratory Belmonte, Salk Institute for Biological Studies)

Abstract

Glioma tumour-initiating cells (GTICs) can originate upon the transformation of neural progenitor cells (NPCs). Studies on GTICs have focused on primary tumours from which GTICs could be isolated and the use of human embryonic material. Recently, the somatic genomic landscape of human gliomas has been reported. RTK (receptor tyrosine kinase) and p53 signalling were found dysregulated in ∼90% and 86% of all primary tumours analysed, respectively. Here we report on the use of human-induced pluripotent stem cells (hiPSCs) for modelling gliomagenesis. Dysregulation of RTK and p53 signalling in hiPSC-derived NPCs (iNPCs) recapitulates GTIC properties in vitro. In vivo transplantation of transformed iNPCs leads to highly aggressive tumours containing undifferentiated stem cells and their differentiated derivatives. Metabolic modulation compromises GTIC viability. Last, screening of 101 anti-cancer compounds identifies three molecules specifically targeting transformed iNPCs and primary GTICs. Together, our results highlight the potential of hiPSCs for studying human tumourigenesis.

Suggested Citation

  • Ignacio Sancho-Martinez & Emmanuel Nivet & Yun Xia & Tomoaki Hishida & Aitor Aguirre & Alejandro Ocampo & Li Ma & Robert Morey & Marie N. Krause & Andreas Zembrzycki & Olaf Ansorge & Eric Vazquez-Ferr, 2016. "Establishment of human iPSC-based models for the study and targeting of glioma initiating cells," Nature Communications, Nature, vol. 7(1), pages 1-14, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10743
    DOI: 10.1038/ncomms10743
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