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

Visualizing Engrafted Human Cancer and Therapy Responses in Immunodeficient Zebrafish.

Author information

1
Molecular Pathology Unit, Massachusetts General Hospital Research Institute, Charlestown, MA 02129, USA; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02139, USA.
2
Molecular Pathology Unit, Massachusetts General Hospital Research Institute, Charlestown, MA 02129, USA; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Bethesda, MD 20815, USA.
3
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
4
Molecular Pathology Unit, Massachusetts General Hospital Research Institute, Charlestown, MA 02129, USA; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
5
Shriners Hospitals for Children-Boston, MA 02114, USA; Center for Engineering in Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02114, USA.
6
Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
7
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Howard Hughes Medical Institute, Bethesda, MD 20815, USA.
8
Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA.
9
Molecular Pathology Unit, Massachusetts General Hospital Research Institute, Charlestown, MA 02129, USA; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02139, USA. Electronic address: dlangenau@mgh.harvard.edu.

Abstract

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

Comment in

PMID:
31031007
PMCID:
PMC6570580
[Available on 2020-06-13]
DOI:
10.1016/j.cell.2019.04.004

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