Establishment of tractable human iPSC-based models for the study and targeting of glioma initiation (Expression)

Gliomas can originate upon transformation of adult Neural Progenitor Cells (NPCs) to Tumor Initiating Cells (TICs). Studies on human Glioma TICs (GTICs) have focused on the use of primary tumors from which GTICs could be isolated. Therefore investigations on the driver events underlying NPC transformation and human glioma initiation remain limited to the use of human embryonic material. Here we report on the development of strategies for the modeling of human gliomagenesis based on the use of human induced Pluripotent Stem Cells (hiPSCs). Transformation of hiPSC-derived NPCs (iNPCs) by defined genetic alterations led to the establishment of tractable human GTIC models suitable for studying the early steps of gliomagenesis as well as for screening studies. Dysregulation of PI3K, MAPK and p53 signaling in iNPCs led to the acquisition of functional GTIC properties. In vivo transplantation led to the formation of highly aggressive, infiltrative and heterogeneous tumors upon limited dilutions and secondary transplantation, faithfully recapitulating gliomagenesis. Metabolic modulation by chemical approaches compromised GTIC viability. Pilot screening of 101 anti-cancer compounds identified 3 molecules specifically targeting transformed iNPCs and primary GTICs. Together, our results demonstrate the potential of hiPSCs for the functional testing of putative driver mutations underlying human tumorigenesis and pave new avenues for the development of personalized cancer therapeutics.

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Sancho-Martinez I, Nivet E, Xia Y, Hishida T, Aguirre A, Ocampo A, Ma L, Morey R, Krause MN, Zembrzycki A, Ansorge O, Vazquez-Ferrer E, Dubova I, Reddy P, Lam D, Hishida Y, Wu MZ, Esteban CR, O'Leary D, Wahl GM, Verma IM, Laurent LC, Izpisua Belmonte JC