title: Orthotopic models of pediatric brain tumors in zebrafish.
abstract: High-throughput screens (HTS) of compound toxicity against cancer cells can identify thousands of potential new drug-leads. But only limited numbers of these compounds can progress to expensive and labor-intensive efficacy studies in mice, creating a 'bottle neck' in the drug development pipeline. Approaches that triage drug-leads for further study are greatly needed. Here we provide an intermediary platform between HTS and mice by adapting mouse models of pediatric brain tumors to grow as orthotopic xenografts in the brains of zebrafish. Freshly isolated mouse ependymoma, glioma and choroid plexus carcinoma cells expressing red fluorescence protein were conditioned to grow at 34 °C. Conditioned tumor cells were then transplanted orthotopically into the brains of zebrafish acclimatized to ambient temperatures of 34 °C. Live in vivo fluorescence imaging identified robust, quantifiable and reproducible brain tumor growth as well as spinal metastasis in zebrafish. All tumor xenografts in zebrafish retained the histological characteristics of the corresponding parent mouse tumor and efficiently recruited fish endothelial cells to form a 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 models can effectively assess drug efficacy. Our data demonstrate, for the first time, that mouse brain tumors can grow orthotopically in fish and serve as a platform to study drug efficacy. As large cohorts of brain tumor-bearing zebrafish can be generated rapidly and inexpensively, these models may serve as a powerful tool to triage drug-leads from HTS for formal efficacy testing in mice.
authors.affiliation: Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Eden
authors.affiliation: Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: B
authors.initials: B
authors.lastname: Ju
authors.affiliation: Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: M
authors.initials: M
authors.lastname: Murugesan
authors.affiliation: Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: T N
authors.initials: TN
authors.lastname: Phoenix
authors.affiliation: Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: B
authors.initials: B
authors.lastname: Nimmervoll
authors.affiliation: Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Tong
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: D W
authors.initials: DW
authors.lastname: Ellison
authors.affiliation: Department of Computational Biology and Bioinformatics, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: D
authors.initials: D
authors.lastname: Finkelstein
authors.affiliation: Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: K
authors.initials: K
authors.lastname: Wright
authors.affiliation: Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: N
authors.initials: N
authors.lastname: Boulos
authors.affiliation: Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: J
authors.initials: J
authors.lastname: Dapper
authors.affiliation: Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: R
authors.initials: R
authors.lastname: Thiruvenkatam
authors.affiliation: Department of Biological Sciences, University of Memphis, Memphis, TN, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Lessman
authors.affiliation: Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Taylor
authors.affiliation: Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Gilbertson
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology*; D002648:Child; D004195:Disease Models, Animal; D055808:Drug Discovery; D005910:Glioma / Q000473:pathology*; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D059467:Transcriptome; D014183:Transplantation, Heterologous; D015027:Zebrafish
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