title: Establishment of human iPSC-based models for the study and targeting of glioma initiating cells.
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.
authors.affiliation: Gene Expression Laboratory Belmonte, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Ignacio
authors.identifier: http://orcid.org/0000-0003-4348-1038
authors.initials: I
authors.lastname: Sancho-Martinez
authors.affiliation: Gene Expression Laboratory Belmonte, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Nivet
authors.affiliation: Gene Expression Laboratory Belmonte, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Gene Expression Laboratory Belmonte, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Hishida
authors.affiliation: Gene Expression Laboratory Belmonte, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Aitor
authors.initials: A
authors.lastname: Aguirre
authors.affiliation: Gene Expression Laboratory Belmonte, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Ocampo
authors.affiliation: Gene Expression Laboratory Belmonte, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.|Universidad Católica San Antonio de Murcia (UCAM) Campus de los Jerónimos, N° 135 Guadalupe, Murcia 30107, Spain.
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Reproductive Medicine, University of California, San Diego, Sanford Consortium for Regenerative Medicine, 2880 Torrey Pines Scenic Drive, La Jolla, California 92037, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Morey
authors.affiliation: Gene Expression Laboratory Belmonte, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Marie N
authors.initials: MN
authors.lastname: Krause
authors.affiliation: Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Andreas
authors.identifier: http://orcid.org/0000-0001-8468-4195
authors.initials: A
authors.lastname: Zembrzycki
authors.affiliation: Department of Neuropathology, West Wing, Level 1, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Olaf
authors.initials: O
authors.lastname: Ansorge
authors.affiliation: Gene Expression Laboratory Belmonte, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Vazquez-Ferrer
authors.affiliation: Gene Expression Laboratory Belmonte, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.|Universidad Católica San Antonio de Murcia (UCAM) Campus de los Jerónimos, N° 135 Guadalupe, Murcia 30107, Spain.
authors.forename: Ilir
authors.initials: I
authors.lastname: Dubova
authors.affiliation: Gene Expression Laboratory Belmonte, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Pradeep
authors.identifier: http://orcid.org/0000-0002-9173-3845
authors.initials: P
authors.lastname: Reddy
authors.affiliation: Gene Expression Laboratory Belmonte, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: David
authors.initials: D
authors.lastname: Lam
authors.affiliation: Gene Expression Laboratory Belmonte, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Hishida
authors.affiliation: Gene Expression Laboratory Belmonte, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Min-Zu
authors.initials: MZ
authors.lastname: Wu
authors.affiliation: Gene Expression Laboratory Belmonte, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Concepcion Rodriguez
authors.initials: CR
authors.lastname: Esteban
authors.affiliation: Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: O'Leary
authors.affiliation: Gene Expression Laboratory Wahl, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Geoffrey M
authors.initials: GM
authors.lastname: Wahl
authors.affiliation: Laboratory of Genetics, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Inder M
authors.initials: IM
authors.lastname: Verma
authors.affiliation: Department of Reproductive Medicine, University of California, San Diego, Sanford Consortium for Regenerative Medicine, 2880 Torrey Pines Scenic Drive, La Jolla, California 92037, USA.
authors.forename: Louise C
authors.initials: LC
authors.lastname: Laurent
authors.affiliation: Gene Expression Laboratory Belmonte, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Izpisua Belmonte
mesh_terms: D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D005260:Female; D005910:Glioma / Q000209:etiology*; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D008297:Male; D014411:Neoplastic Stem Cells / Q000502:physiology*; D058953:Neural Stem Cells / Q000502:physiology*; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D014410:Tumor Stem Cell Assay
chemical_list: C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors