Cancer avatars derived from genetically engineered pluripotent stem cells allow for longitudinal assessment of tumor development

Many current cellular models aimed to elucidate 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 the neural progenitor cells derived from hiPSCs introduced with tumor-associated genetic driver mutations revealed by The Cancer Genome Atlas project for glioblastoma (GBM) results in formation of brain tumors. 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 these tumor cells generate 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. Overall design: Analyses on inter- and intra-tumor heterogeneity of different glioblastoma derived from differentially engineered isogenic human induced pluripotent stem cells.