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.
Bibliographical noteFunding Information:
We thank W.K. Cavenee, A.H. Thorne, C. Zanca, Yeo lab and Furnari lab members for discussions and helpful suggestions. We are grateful to the IGM Genomics Center, University of California San Diego for conducting RNA sequencing, digital karyotyping, single-cell RNA sequencing and whole genome sequencing. We thank D. Pizzo at the Center for Advanced Laboratory Medicine, University of California San Diego for assistance with immunohistochemistry. This work was supported by National Institutes of Health (NIH) R01NS080939 (F.B.F.), R01HL137223 and R01HD85902 (G.W.Y.), R01GM114362 (V.B. and N.D.N.), P30CA023100 (IGM Genomics Center), the Defeat GBM Research Collaborative, a subsidiary of the National Brain Tumor Society (F.B.F. and P.S.M.), Ruth L. Kirschstein Institutional National Research Award T32 GM008666 (A.D.P.), grants from National Institute of Neurological Disorders and Stroke NS73831 (P.S.M.), the Ben and Catherine Ivy Foundation (P.S.M.), and National Science Foundation DBI-1458557 (V.B. and N.D.N.). I.A.C. is a San Diego IRACDA Fellow supported by NIH/NIGMS K12 GM068524 Award.
© 2020, The Author(s).
PubMed: MeSH publication types
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