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. Wahl; Inder M. Verma; Louise C. Laurent; Juan Carlos Izpisua Belmonte

doi:10.1038/ncomms10743

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

Biological, Environmental Sciences and Engineering

Research output: Contribution to journal › Article › peer-review

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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 language	English (US)
Article number	10743
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms10743
State	Published - Feb 22 2016

ASJC Scopus subject areas

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Sancho-Martinez, I., Nivet, E., Xia, Y., Hishida, T., Aguirre, A., Ocampo, A., Ma, L., Morey, R., Krause, M. N., Zembrzycki, A., Ansorge, O., Vazquez-Ferrer, E., Dubova, I., Reddy, P., Lam, D., Hishida, Y., Wu, M. Z., Esteban, C. R., Oleary, D., ... Izpisua Belmonte, J. C. (2016). Establishment of human iPSC-based models for the study and targeting of glioma initiating cells. Nature Communications, 7, Article 10743. https://doi.org/10.1038/ncomms10743

@article{3cf29fc11981472f9030c4c31ee0779e,

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 {\^a}1/490% 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.",

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

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.",

year = "2016",

month = feb,

day = "22",

doi = "10.1038/ncomms10743",

language = "English (US)",

volume = "7",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

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, Oleary, D, Wahl, GM, Verma, IM, Laurent, LC & Izpisua Belmonte, JC 2016, 'Establishment of human iPSC-based models for the study and targeting of glioma initiating cells', Nature Communications, vol. 7, 10743. https://doi.org/10.1038/ncomms10743

TY - JOUR

T1 - Establishment of human iPSC-based models for the study and targeting of glioma initiating cells

AU - Sancho-Martinez, Ignacio

AU - Nivet, Emmanuel

AU - Xia, Yun

AU - Hishida, Tomoaki

AU - Aguirre, Aitor

AU - Ocampo, Alejandro

AU - Ma, Li

AU - Morey, Robert

AU - Krause, Marie N.

AU - Zembrzycki, Andreas

AU - Ansorge, Olaf

AU - Vazquez-Ferrer, Eric

AU - Dubova, Ilir

AU - Reddy, Pradeep

AU - Lam, David

AU - Hishida, Yuriko

AU - Wu, Min Zu

AU - Esteban, Concepcion Rodriguez

AU - Oleary, Dennis

AU - Wahl, Geoffrey M.

AU - Verma, Inder M.

AU - Laurent, Louise C.

AU - Izpisua Belmonte, Juan Carlos

N1 - 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.

PY - 2016/2/22

Y1 - 2016/2/22

N2 - 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.

AB - 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.

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U2 - 10.1038/ncomms10743

DO - 10.1038/ncomms10743

M3 - Article

C2 - 26899176

AN - SCOPUS:84959017857

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 10743

ER -

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

Abstract

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UN SDGs

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