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Generation of Subcutaneous and Intrahepatic Human Hepatocellular Carcinoma Xenografts in Immunodeficient Mice
Published on: September 25, 2013
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Visualizing Engrafted Human Cancer and Therapy Responses in Immunodeficient Zebrafish
Chuan Yan1, Dalton C Brunson2, Qin Tang2
1Molecular 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.
Cell
|April 30, 2019
Summary
We developed an optically-clear zebrafish model for dynamic, single-cell visualization of human cancer xenografts. This model revealed combination therapy efficacy for rhabdomyosarcoma by tracking cell cycle arrest and apoptosis.
Area of Science:
- Comparative immunology
- Cancer biology
- Zebrafish models
Background:
- Xenograft models are crucial for cancer drug preclinical efficacy assessment.
- Direct single-cell phenotype visualization in xenografts remains challenging.
Purpose of the Study:
- To develop an optically-clear zebrafish xenograft model for dynamic single-cell visualization of human cancers.
- To assess preclinical efficacy of combination therapy for rhabdomyosarcoma.
Main Methods:
- Utilized prkdc-/-; il2rga-/- zebrafish lacking adaptive and NK immune cells for xenotransplantation.
- Employed photoconversion cell-lineage tracing and FUCCI cell-cycle reporters for dynamic imaging.
- Administered combination olaparib (PARP inhibitor) and temozolomide (DNA-damaging agent) therapy.
Main Results:
- Successfully engrafted diverse human cancers in zebrafish at 37°C, enabling single-cell visualization.
- Identified migratory and proliferative cell states in human rhabdomyosarcoma.
- Demonstrated combination therapy arrested rhabdomyosarcoma cells in G2 phase, preceding apoptosis.
- Showcased successful engraftment of patient-derived xenografts.
Conclusions:
- The developed zebrafish model offers dynamic, single-cell resolution for cancer xenografts.
- Combination olaparib and temozolomide shows preclinical efficacy against rhabdomyosarcoma.
- This model facilitates personalized therapeutic development for various cancers.
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