Longitudinal assessment of tumor development using cancer avatars derived from genetically engineered pluripotent stem cells

• Published in: Nature communications Vol. 11; no. 1; p. 550
• Main Authors: Koga, Tomoyuki, Chaim, Isaac A, Benitez, Jorge A, Markmiller, Sebastian, Parisian, Alison D, Hevner, Robert F, Turner, Kristen M, Hessenauer, Florian M, D'Antonio, Matteo, Nguyen, Nam-Phuong D, Saberi, Shahram, Ma, Jianhui, Miki, Shunichiro, Boyer, Antonia D, Ravits, John, Frazer, Kelly A, Bafna, Vineet, Chen, Clark C, Mischel, Paul S, Yeo, Gene W, Furnari, Frank B
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 28.01.2020; Nature Publishing Group UK; Nature Portfolio
• Subjects: Animals; Avatars; Brain cancer; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Cancer; Cell culture; Cell Differentiation; Cell Line, Tumor; Deoxyribonucleic acid; DNA; Female; Gene Expression Regulation, Neoplastic; Genetic Engineering; Genome; Genomes; Glioblastoma; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Glioma - genetics; Glioma - pathology; Heterogeneity; Humans; Mice; Mice, SCID; Mutation; Neoplasm Transplantation; Neoplastic Stem Cells - pathology; Neural stem cells; Neurofibromin 1 - genetics; Neurospheres; Pluripotency; Pluripotent Stem Cells - pathology; Progenitor cells; PTEN Phosphohydrolase - genetics; Stem cells; Transplantation, Heterologous; Tumor Suppressor Protein p53 - genetics; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-14312-1

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.