Visualizing Engrafted Human Cancer and Therapy Responses in Immunodeficient Zebrafish

Publication date: Available online 25 April 2019Source: CellAuthor(s): 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. KarabacakSummaryXenograft 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, o...
Source: Cell - Category: Cytology Source Type: research