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

authors

  • Sancho-Martinez Ignacio
  • Nivet Emmanuel
  • Xia Yun
  • Hishida ă Tomoaki
  • Aguirre Aitor
  • Ocampo Alejandro
  • Ma Li
  • Morey ă Robert
  • Krause Marie N.
  • Zembrzycki Andreas
  • Ansorge Olaf ă
  • Vazquez-Ferrer Eric
  • Dubova Ilir
  • Reddy Pradeep
  • Lam ă David
  • Hishida Yuriko
  • Wu Min-Zu
  • Esteban Concepcion ă Rodriguez
  • O'Leary Dennis
  • Wahl Geoffrey M.
  • Verma Inder M. ă
  • Laurent Louise C.
  • Belmonte Juan Carlos Izpisua

abstract

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

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