Visualizing Engrafted Human Cancer and Therapy Responses in Immunodeficient Zebrafish

Cell. 2019 Jun 13;177(7):1903-1914.e14. doi: 10.1016/j.cell.2019.04.004. Epub 2019 Apr 25.


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.

Keywords: SCID; breast cancer; il2rg; immune deficient; melanoma; prkdc; rhabdomyosarcoma; xenograft; zebrafish.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified / genetics
  • Animals, Genetically Modified / immunology
  • Animals, Genetically Modified / metabolism*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Female
  • Heterografts
  • Humans
  • K562 Cells
  • Male
  • Muscle Neoplasms* / drug therapy
  • Muscle Neoplasms* / immunology
  • Muscle Neoplasms* / metabolism
  • Muscle Neoplasms* / pathology
  • Neoplasm Transplantation
  • Phthalazines / pharmacology
  • Piperazines / pharmacology
  • Rhabdomyosarcoma* / drug therapy
  • Rhabdomyosarcoma* / immunology
  • Rhabdomyosarcoma* / metabolism
  • Rhabdomyosarcoma* / pathology
  • Temozolomide / pharmacology
  • Xenograft Model Antitumor Assays
  • Zebrafish / genetics
  • Zebrafish / immunology
  • Zebrafish / metabolism*


  • Phthalazines
  • Piperazines
  • olaparib
  • Temozolomide