Visualizing Engrafted Human Cancer and Therapy Responses in Immunodeficient Zebrafish

Chuan Yan, Dalton C. Brunson, Qin Tang, Daniel Do, Nicolae A. Iftimia, John C. Moore, Madeline N. Hayes, Alessandra M. Welker, Elaine G. Garcia, Taronish D. Dubash, Xin Hong, Benjamin J. Drapkin, David T. Myers, Sarah Phat, Angela Volorio, Dieuwke L. Marvin, Matteo Ligorio, Lyle Dershowitz, Karin M. McCarthy, Murat N. KarabacakJonathan A. Fletcher, Dennis C. Sgroi, John A. Iafrate, Shyamala Maheswaran, Nick J. Dyson, Daniel A. Haber, John F. Rawls, David M. Langenau

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Xenograft cell transplantation into immunodeficient mice has become the gold standard for assessing pre-clinical efficacy of cancer drugs, yet direct visualization of single-cell phenotypes is difficult. Here, we report an optically-clear prkdc−/−, il2rga−/− zebrafish that lacks adaptive and natural killer immune cells, can engraft a wide array of human cancers at 37°C, and permits the dynamic visualization of single engrafted cells. For example, photoconversion cell-lineage tracing identified migratory and proliferative cell states in human rhabdomyosarcoma, a pediatric cancer of muscle. Additional experiments identified the preclinical efficacy of combination olaparib PARP inhibitor and temozolomide DNA-damaging agent as an effective therapy for rhabdomyosarcoma and visualized therapeutic responses using a four-color FUCCI cell-cycle fluorescent reporter. These experiments identified that combination treatment arrested rhabdomyosarcoma cells in the G2 cell cycle prior to induction of apoptosis. Finally, patient-derived xenografts could be engrafted into our model, opening new avenues for developing personalized therapeutic approaches in the future.

Original languageEnglish (US)
Pages (from-to)1903-1914.e14
JournalCell
Volume177
Issue number7
DOIs
StatePublished - Jun 13 2019
Externally publishedYes

Keywords

  • SCID
  • breast cancer
  • il2rg
  • immune deficient
  • melanoma
  • prkdc
  • rhabdomyosarcoma
  • xenograft
  • zebrafish

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Yan, C., Brunson, D. C., Tang, Q., Do, D., Iftimia, N. A., Moore, J. C., Hayes, M. N., Welker, A. M., Garcia, E. G., Dubash, T. D., Hong, X., Drapkin, B. J., Myers, D. T., Phat, S., Volorio, A., Marvin, D. L., Ligorio, M., Dershowitz, L., McCarthy, K. M., ... Langenau, D. M. (2019). Visualizing Engrafted Human Cancer and Therapy Responses in Immunodeficient Zebrafish. Cell, 177(7), 1903-1914.e14. https://doi.org/10.1016/j.cell.2019.04.004