Glioblastomas derived from genetically modified pluripotent stem cells recapitulate pathobiology

Koga, T.; Benitez, J. A.; Chaim, I. A.; Markmiller, S.; Parisian, A. D.; Turner, K. M.; Hessenauer, F. M.; D'Antonio, M.; Nguyen, N.-p. D.; Saberi, S.; Ma, J.; Miki, S.; Boyer, A. D.; Ravits, J.; Frazer, K. A.; Bafna, V.; Chen, C. C.; Mischel, P. S.; Yeo, G. W.; Furnari, F. B.

doi:10.1101/576009

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bioRxiv · 10.1101/576009

Glioblastomas derived from genetically modified pluripotent stem cells recapitulate pathobiology

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Abstract

Many current cellular models aimed at elucidating cancer biology do not recapitulate pathobiology including tumor heterogeneity, an inherent feature of cancer that underlies treatment resistance. Here we introduce a new cancer modeling paradigm using genetically engineered human pluripotent stem cells (hiPSCs) that capture authentic cancer pathobiology. Orthotopic engraftment of neural progenitor cells derived from hiPSCs that have been genome-edited to contain tumor-associated genetic driver mutations revealed by The Cancer Genome Atlas project for glioblastoma (GBM) result in formation of high-grade gliomas. As observed in GBM patient samples, these models harbor inter-tumor heterogeneity resembling different GBM molecular subtypes, and intra-tumor heterogeneity. Further, re-engraftment of primary tumor neurospheres generates secondary tumors with features characteristic of patient samples and present mutation-dependent patterns of tumor evolution. Thus, these cancer avatar models provide a platform for a comprehensive longitudinal assessment of human tumor development as governed by molecular subtype mutations and lineage-restricted differentiation.

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Koga, T., Benitez, J. A., Chaim, I. A., Markmiller, S., Parisian, A. D., Turner, K. M., Hessenauer, F. M., D'Antonio, M., Nguyen, N.-p. D., Saberi, S., Ma, J., Miki, S., Boyer, A. D., Ravits, J., Frazer, K. A., Bafna, V., Chen, C. C., Mischel, P. S., Yeo, G. W., Furnari, F. B.. 2019-03-13. Glioblastomas derived from genetically modified pluripotent stem cells recapitulate pathobiology. https://doi.org/10.1101/576009

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