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

Tomoyuki Koga, Isaac A. Chaim, Jorge A. Benitez, Sebastian Markmiller, Alison D. Parisian, Robert F. Hevner, Kristen M. Turner, Florian M. Hessenauer, Matteo D’Antonio, Nam phuong D. Nguyen, Shahram Saberi, Jianhui Ma, Shunichiro Miki, Antonia D. Boyer, John Ravits, Kelly A. Frazer, Vineet Bafna, Clark C. Chen, Paul S. Mischel, Gene W. YeoFrank B. Furnari

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number550
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Jan 28 2020

Bibliographical note

Publisher Copyright:
© 2020, The Author(s).

Keywords

  • Animals
  • Brain Neoplasms/genetics
  • Cell Differentiation
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genetic Engineering
  • Genome
  • Glioblastoma/genetics
  • Glioma/genetics
  • Humans
  • Mice
  • Mice, SCID
  • Mutation
  • Neoplasm Transplantation
  • Neoplastic Stem Cells/pathology
  • Neurofibromin 1/genetics
  • PTEN Phosphohydrolase/genetics
  • Pluripotent Stem Cells/pathology
  • Transplantation, Heterologous
  • Tumor Suppressor Protein p53/genetics

PubMed: MeSH publication types

  • Journal Article

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