Glioblastomas derived from genetically modified pluripotent stem cells recapitulate pathobiology
bioRxiv(2019)
摘要
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.
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