ZFIN ID: ZDB-PUB-190430-2
Visualizing Engrafted Human Cancer and Therapy Responses in Immunodeficient Zebrafish
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., Karabacak, M.N., Fletcher, J.A., Sgroi, D.C., Iafrate, J.A., Maheswaran, S., Dyson, N.J., Haber, D.A., Rawls, J.F., Langenau, D.M.
Date: 2019
Source: Cell   177(7): 1903-1914.e14 (Journal)
Registered Authors: Hayes, Madeline, Langenau, David, Moore, John, Rawls, John F., Tang, Qin
Keywords: SCID, breast cancer, il2rg, immune deficient, melanoma, prkdc, rhabdomyosarcoma, xenograft, zebrafish
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*
PubMed: 31031007 Full text @ Cell
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.