4 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:948-953.

Highlights d Phosphorylation of PTEN at tyrosine 240 (pY240) by FGFR2 mediates IR resistance d pY240-PTEN plays a critical role in DNA damage repair d pY240-PTEN associates with chromatin DNA through interaction with Ki-67 d Blocking pY240-PTEN using FGFR inhibitors sensitizes tumors to ionizing radiation

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 genomeedited 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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