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Nat Commun ; 11(1): 550, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31992716

RESUMO

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.


Assuntos
Engenharia Genética , Glioblastoma/genética , Glioblastoma/patologia , Células-Tronco Pluripotentes/patologia , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Diferenciação Celular , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Genoma , Glioblastoma/metabolismo , Glioma/genética , Glioma/patologia , Humanos , Camundongos , Camundongos SCID , Mutação , Transplante de Neoplasias , Células-Tronco Neoplásicas/patologia , Neurofibromina 1/genética , PTEN Fosfo-Hidrolase/genética , Transplante Heterólogo , Proteína Supressora de Tumor p53/genética
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