Date of Award
Doctor of Philosophy
High-throughput screens (HTS) of compound toxicity against cancer cells in vitro can identify thousands of potential new drug-leads. But only limited numbers of these lead compounds can progress to expensive and labor intensive in vivo efficacy studies in mice, creating a ‘bottle-neck’ in the drug development pipeline. Experimental systems to triage HTS leads for further study are greatly needed. Here, we adapted a series of accurate mouse models of pediatric brain tumors to grow as orthotopic implants in the brains of zebrafish. Freshly isolated mouse ependymoma, glioma and choroid plexus carcinoma cells expressing red fluorescence protein (RFP) were acclimatized to grow at 28oC. Tumor cells were then transplanted orthotopically into the brains of zebrafish. Live in vivo fluorescence imaging identified robust, quantifiable and reproducible brain tumor growth as well as spinal metastasis in zebrafish. Tumor xenografts also retained the histological and transcriptomic characteristics of the corresponding mouse parent tumor and efficiently recruited fish endothelial cells to form a typical tumor vasculature. Finally, by treating zebrafish harboring ERBB2-driven gliomas with an appropriate cytotoxic chemotherapy (5-fluorouracil) or tyrosine kinase inhibitor (Erlotinib), we show that these model systems can effectively test drug efficacy and pharmacodynamic activity. Our data demonstrate, for the first time, that mouse models of brain tumors can be orthtopically transplanted into fish and serve as a platform to study drug efficacy. Since large cohorts of brain tumor bearing zebrafish can be generated rapidly and inexpensively, these models may serve as a powerful tool to triage HTS ‘hits’ for formal efficacy testing in mice.
Dissertation or thesis originally submitted to the local University of Memphis Electronic Theses & dissertation (ETD) Repository.
Eden, Christopher James, "Orthotopic Models of Pediatric Brain Tumors in Zebrafish" (2014). Electronic Theses and Dissertations. 881.