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Koga, Tomoyuki; Chaim, Isaac A; Benitez, Jorge A; Markmiller, Sebastian; Parisian, Alison D; Hevner, Robert F; Turner, Kristen M; Hessenauer, Florian M; D'Antonio, Matteo; Nguyen, Nam-Phuong D; Saberi, Shahram; Ma, Jianhui; Miki, Shunichiro; Boyer, Antonia D; Ravits, John; Frazer, Kelly A; Bafna, Vineet; Chen, Clark C; Mischel, Paul S; Yeo, Gene W; Furnari, Frank B
Nature communications, 01/2020, Letnik: 11, Številka: 1Journal Article
Many 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 cancer modeling paradigm using genetically engineered human pluripotent stem cells (hiPSCs) that captures authentic cancer pathobiology. Orthotopic engraftment of the 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) results in formation of high-grade gliomas. Similar to patient-derived GBM, these models harbor inter-tumor heterogeneity resembling different GBM molecular subtypes, intra-tumor heterogeneity, and extrachromosomal DNA amplification. Re-engraftment of these primary tumor neurospheres generates secondary tumors with features characteristic of patient samples and present mutation-dependent patterns of tumor evolution. These cancer avatar models provide a platform for comprehensive longitudinal assessment of human tumor development as governed by molecular subtype mutations and lineage-restricted differentiation.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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