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Glioblastomas derived from genetically modified pluripotent stem cells recapitulate pathobiology

View ORCID ProfileTomoyuki Koga, Jorge A. Benitez, Isaac A. Chaim, Sebastian Markmiller, Alison D. Parisian, Kristen M. Turner, Florian M. Hessenauer, Matteo D’Antonio, Namphuong D. Nguyen, Shahram Saberi, Jianhui Ma, Shunichiro Miki, Antonia D. Boyer, John Ravits, Kelly A. Frazer, Vineet Bafna, Clark C. Chen, Paul S. Mischel, Gene W. Yeo, Frank B. Furnari
doi: https://doi.org/10.1101/576009
Tomoyuki Koga
Ludwig Cancer Research, San Diego Branch, La Jolla, CA 92093, USA
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  • ORCID record for Tomoyuki Koga
Jorge A. Benitez
Ludwig Cancer Research, San Diego Branch, La Jolla, CA 92093, USA
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Isaac A. Chaim
Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA
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Sebastian Markmiller
Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA
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Alison D. Parisian
Ludwig Cancer Research, San Diego Branch, La Jolla, CA 92093, USADepartment of Pathology, University of California at San Diego, La Jolla, CA 92093, USA
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Kristen M. Turner
Ludwig Cancer Research, San Diego Branch, La Jolla, CA 92093, USA
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Florian M. Hessenauer
Ludwig Cancer Research, San Diego Branch, La Jolla, CA 92093, USA
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Matteo D’Antonio
Institute for Genomic Medicine, University of California at San Diego, La Jolla, CA 92093, USA
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Namphuong D. Nguyen
Department of Computer Science and Engineering, University of California at San Diego, La Jolla, CA 92093, USA
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Shahram Saberi
Department of Neuroscience, University of California at San Diego, La Jolla, CA 92093, USA
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Jianhui Ma
Ludwig Cancer Research, San Diego Branch, La Jolla, CA 92093, USA
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Shunichiro Miki
Ludwig Cancer Research, San Diego Branch, La Jolla, CA 92093, USA
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Antonia D. Boyer
Ludwig Cancer Research, San Diego Branch, La Jolla, CA 92093, USA
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John Ravits
Department of Neuroscience, University of California at San Diego, La Jolla, CA 92093, USA
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Kelly A. Frazer
Institute for Genomic Medicine, University of California at San Diego, La Jolla, CA 92093, USADepartment of Pediatrics and Rady Children’s Hospital, University of California at San Diego, La Jolla, CA 92093, USA
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Vineet Bafna
Department of Computer Science and Engineering, University of California at San Diego, La Jolla, CA 92093, USA
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Clark C. Chen
Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455, USA
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Paul S. Mischel
Ludwig Cancer Research, San Diego Branch, La Jolla, CA 92093, USADepartment of Pathology, University of California at San Diego, La Jolla, CA 92093, USA
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Gene W. Yeo
Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA
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  • For correspondence: ffurnari@ucsd.edu geneyeo@ucsd.edu
Frank B. Furnari
Ludwig Cancer Research, San Diego Branch, La Jolla, CA 92093, USADepartment of Pathology, University of California at San Diego, La Jolla, CA 92093, USA
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  • For correspondence: ffurnari@ucsd.edu geneyeo@ucsd.edu
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Abstract

Glioblastoma (GBM) is the most common malignant brain tumor, and particularly difficult to treat due to its inherent heterogeneity, which is promoted by a variety of genetic drivers. A lack of models that robustly recapitulate heterogeneity has been a major obstacle for research progress on this disease. Here we show that neural progenitor cells derived from human induced pluripotent stem cells, CRISPR/Cas9 engineered with different combinations of authentic GBM-related genetic drivers give rise to GBM models that recapitulate the pathobiology of this tumor, including inter- and intra-tumor heterogeneity, differential drug sensitivity, extrachromosomal DNA amplifications, and rapid clonal evolution. Different models established with this approach could serve as a platform for longitudinal assessment of drug treatment sensitivity governed by subtype-specific driver mutations.

One Sentence Summary hiPSC-derived GBMs recapitulate disease.

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Posted March 13, 2019.
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Glioblastomas derived from genetically modified pluripotent stem cells recapitulate pathobiology
Tomoyuki Koga, Jorge A. Benitez, Isaac A. Chaim, Sebastian Markmiller, Alison D. Parisian, Kristen M. Turner, Florian M. Hessenauer, Matteo D’Antonio, Namphuong D. Nguyen, Shahram Saberi, Jianhui Ma, Shunichiro Miki, Antonia D. Boyer, John Ravits, Kelly A. Frazer, Vineet Bafna, Clark C. Chen, Paul S. Mischel, Gene W. Yeo, Frank B. Furnari
bioRxiv 576009; doi: https://doi.org/10.1101/576009
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Glioblastomas derived from genetically modified pluripotent stem cells recapitulate pathobiology
Tomoyuki Koga, Jorge A. Benitez, Isaac A. Chaim, Sebastian Markmiller, Alison D. Parisian, Kristen M. Turner, Florian M. Hessenauer, Matteo D’Antonio, Namphuong D. Nguyen, Shahram Saberi, Jianhui Ma, Shunichiro Miki, Antonia D. Boyer, John Ravits, Kelly A. Frazer, Vineet Bafna, Clark C. Chen, Paul S. Mischel, Gene W. Yeo, Frank B. Furnari
bioRxiv 576009; doi: https://doi.org/10.1101/576009

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