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

authors

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

keywords

• Cell signalling
• CNS cancer
• Cancer models

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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