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

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-Ferrer, Ilir Dubova, Pradeep Reddy, David Lam, Yuriko Hishida, Min-Zu Wu, Concepcion Rodriguez Esteban, Dennis O’Leary, Geoffrey M. Wahl, Inder M. Verma, Louise C. Laurent and Juan Carlos Izpisua Belmonte ()
Additional contact information
Ignacio Sancho-Martinez: Gene Expression Laboratory Belmonte, Salk Institute for Biological Studies
Emmanuel Nivet: Gene Expression Laboratory Belmonte, Salk Institute for Biological Studies
Yun Xia: Gene Expression Laboratory Belmonte, Salk Institute for Biological Studies
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
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
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

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10743

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