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. Yeo () and Frank B. Furnari ()
Additional contact information
Tomoyuki Koga: Ludwig Cancer Research San Diego Branch
Isaac A. Chaim: University of California San Diego
Jorge A. Benitez: Ludwig Cancer Research San Diego Branch
Sebastian Markmiller: University of California San Diego
Alison D. Parisian: Ludwig Cancer Research San Diego Branch
Robert F. Hevner: University of California San Diego
Kristen M. Turner: Ludwig Cancer Research San Diego Branch
Florian M. Hessenauer: Ludwig Cancer Research San Diego Branch
Matteo D’Antonio: University of California San Diego
Nam-phuong D. Nguyen: University of California San Diego
Shahram Saberi: University of California San Diego
Jianhui Ma: Ludwig Cancer Research San Diego Branch
Shunichiro Miki: Ludwig Cancer Research San Diego Branch
Antonia D. Boyer: Ludwig Cancer Research San Diego Branch
John Ravits: University of California San Diego
Kelly A. Frazer: University of California San Diego
Vineet Bafna: University of California San Diego
Clark C. Chen: University of Minnesota
Paul S. Mischel: Ludwig Cancer Research San Diego Branch
Gene W. Yeo: University of California San Diego
Frank B. Furnari: Ludwig Cancer Research San Diego Branch

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14312-1

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DOI: 10.1038/s41467-020-14312-1

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