Visualizing Engrafted Human Cancer and Therapy Responses in Immunodeficient Zebrafish.
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.
Yan, C; Brunson, DC; Tang, Q; Do, D; Iftimia, NA; Moore, JC; Hayes, MN; Welker, AM; Garcia, EG; Dubash, TD; Hong, X; Drapkin, BJ; Myers, DT; Phat, S; Volorio, A; Marvin, DL; Ligorio, M; Dershowitz, L; McCarthy, KM; Karabacak, MN; Fletcher, JA; Sgroi, DC; Iafrate, JA; Maheswaran, S; Dyson, NJ; Haber, DA; Rawls, JF; Langenau, DM
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