Dataset Information

Visualizing Engrafted Human Cancer and Therapy Responses in Immunodeficient Zebrafish.

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.

SUBMITTER: Yan C

PROVIDER: S-EPMC6570580 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Publications

Visualizing Engrafted Human Cancer and Therapy Responses in Immunodeficient Zebrafish.

Yan Chuan C Brunson Dalton C DC Tang Qin Q Do Daniel D Iftimia Nicolae A NA Moore John C JC Hayes Madeline N MN Welker Alessandra M AM Garcia Elaine G EG Dubash Taronish D TD Hong Xin X Drapkin Benjamin J BJ Myers David T DT Phat Sarah S Volorio Angela A Marvin Dieuwke L DL Ligorio Matteo M Dershowitz Lyle L McCarthy Karin M KM Karabacak Murat N MN Fletcher Jonathan A JA Sgroi Dennis C DC Iafrate John A JA Maheswaran Shyamala S Dyson Nick J NJ Haber Daniel A DA Rawls John F JF Langenau David M DM

Cell 20190425 7

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<sup>-/-</sup>, il2rga<sup>-/-</sup> 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-lineag ...[more]

PMID: 31031007

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Project description:OBJECTIVE:Glucagon-like peptide-1 induces glucose-dependent insulin secretion and, in rodents, increases proliferation and survival of pancreatic beta cells. To investigate the effects on human beta cells, we used immunodeficient mice transplanted with human islets. The goal was to determine whether lixisenatide, a glucagon-like peptide-1 receptor agonist, improves human islet function and survival in vivo. METHODS:Five independent transplant studies were conducted with human islets from five individual donors. Diabetic human islet-engrafted immunodeficient mice were treated with lixisenatide (50, 150, and 500 µg/kg) or vehicle. Islet function was determined by blood glucose, plasma human insulin/C-peptide, and glucose tolerance tests. Grafts were analyzed for total beta- and alpha-cell number, percent proliferation, and levels of apoptosis. RESULTS:Diabetic mice transplanted with marginal human islet mass and treated with lixisenatide were restored to euglycemia more rapidly than vehicle-treated mice. Glucose tolerance tests, human plasma insulin, and glucose-stimulation indices of lixisenatide-treated mice were significantly improved compared to vehicle-treated mice. The percentages of proliferating or apoptotic beta cells at graft recovery were not different between lixisenatide-treated and vehicle-treated mice. Nevertheless, in one experiment we found a significant twofold to threefold increase in human beta-cell numbers in lixisenatide-treated compared to vehicle-treated mice. CONCLUSION:Diabetic human islet-engrafted immunodeficient mice treated with lixisenatide show improved restoration of normoglycemia, human plasma insulin, and glucose tolerance compared to vehicle-treated mice engrafted with the same donor islets. Because the proliferative capacity of human beta cells is limited, improved beta-cell survival coupled with enhanced beta-cell function following lixisenatide treatment may provide the greatest benefit for diabetic patients with reduced functional islet mass.

Dataset Information

Visualizing Engrafted Human Cancer and Therapy Responses in Immunodeficient Zebrafish.

Publications

Visualizing Engrafted Human Cancer and Therapy Responses in Immunodeficient Zebrafish.

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