Visualizing Engrafted Human Cancer and Therapy Responses in Immunodeficient Zebrafish.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • June 13, 2019

Published In

Volume / Issue

  • 177 / 7

Start / End Page

  • 1903 - 1914.e14

PubMed ID

  • 31031007

Pubmed Central ID

  • 31031007

Electronic International Standard Serial Number (EISSN)

  • 1097-4172

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2019.04.004

Language

  • eng

Conference Location

  • United States