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 Oleary, Geoffrey M. WahlInder M. Verma, Louise C. Laurent, Juan Carlos Izpisua Belmonte

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

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 â1/490% 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.

Original languageEnglish (US)
Article number10743
JournalNature Communications
Volume7
DOIs
StatePublished - Feb 22 2016

Bibliographical note

Funding Information:
We thank M. Schwarz for administrative support. Y.X. were partially supported by a postdoctoral training grant from the California Institute for Regenerative Medicine (CIRM). E.N. was partially supported by a F.M. Kirby Foundation postdoctoral fellowship. I.S.-M. was partially supported by a Nomis Foundation postdoctoral fellowship. O.A. is supported by the NIHR Oxford Biomedical Research Centre. We thank the staff at the Institute for Genomic Medicine Genomics Facility at UCSD for running the Infinium HumanMethylation450 BeadChips. We acknowledge the San Diego Supercomputing Center (through an allocation from the eXtreme Science and Engineering Discovery Environment [XSEDE]) for providing HPC resources that have contributed to the research results reported within this paper. We thank David Scott and the Cancer Metabolism Shared Resource in the Sanford-Burnham Medical Research Institute Cancer Center (supported by the NCI under award number 5P30CA030199) for assistance with GC–MS and 13C-labelling experiments. L.M. and I.D. were partially supported by UCAM. R.M. and L.C.L. were supported by the UCSD Department of Reproductive Medicine. G.M.W., I.M.V. and J.C.I.B. are supported by the Cancer Center Core Grant (P30 CA014195-38) and the Leona M. and Harry B. Helmsley Charitable Trust Grant #2012-PG-MED002. I.M.V. is supported in part by grants from the NIH (HL053670) and the H.N. and Frances C. Berger Foundation. Work in the laboratory of J.C.I.B. was supported by grants from NIH (5U01HL107442), CIRM, UCAM and the G. Harold and Leila Y. Mathers Charitable Foundation.

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy

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