Longitudinal assessment of tumor development using cancer avatars derived from genetically engineered pluripotent stem cells
Tomoyuki Koga, Isaac A. Chaim, Jorge A. Benítez, Sebastian Markmiller, Alison D. Parisian, Robert F. Hevner, Kristen M. Turner, Florian Hessenauer, Matteo D’Antonio, Nam Nguyen, Shahram Saberi, Jianhui Ma, Shunichiro Miki, Antonia Boyer, John Ravits, Kelly A. Frazer, Vineet Bafna, Clark C. Chen, Paul S. Mischel, G Yeo, Frank B. Furnari
Abstract
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.