A zebrafish transgenic model of Ewing’s sarcoma reveals conserved mediators of EWS-FLI1 tumorigenesis

Leacock, Stefanie W.; Basse, Audrey N.; Chandler, Garvin L.; Kirk, Anne; Rakheja, Dinesh; Amatruda, James F.

doi:10.1242/dmm.007401

Cited by 63 publications

(46 citation statements)

References 58 publications

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“…The expression of EWS-FLI1 in zebrafish also results in tumor formation, with higher incidences on the p53 null background [33]. However, these models lack the essential elements of tumor initiation, as they are derived from established tumors or cell lines transformed in vitro .…”

Section: Introductionmentioning

confidence: 99%

Combined experience of six independent laboratories attempting to create an Ewing sarcoma mouse model

et al. 2016

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Ewing sarcoma (ES) involves a tumor-specific chromosomal translocation that produces the EWS-FLI1 protein, which is required for the growth of ES cells both in vitro and in vivo. However, an EWS-FLI1-driven transgenic mouse model is not currently available. Here, we present data from six independent laboratories seeking an alternative approach to express EWS-FLI1 in different murine tissues. We used the Runx2, Col1a2.3, Col1a3.6, Prx1, CAG, Nse, NEFL, Dermo1, P0, Sox9 and Osterix promoters to target EWS-FLI1 or Cre expression. Additional approaches included the induction of an endogenous chromosomal translocation, in utero knock-in, and the injection of Cre-expressing adenovirus to induce EWS-FLI1 expression locally in multiple lineages. Most models resulted in embryonic lethality or developmental defects. EWS-FLI1-induced apoptosis, promoter leakiness, the lack of potential cofactors, and the difficulty of expressing EWS-FLI1 in specific sites were considered the primary reasons for the failed attempts to create a transgenic mouse model of ES.

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Section: Introductionmentioning

confidence: 99%

Combined experience of six independent laboratories attempting to create an Ewing sarcoma mouse model

et al. 2016

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“…94 In addition, a zebrafish model transgenic for the human EWS-FLI1 fusion was recently found to develop small round blue cell tumors at low incidence. 62 …”

Section: C-mycmentioning

confidence: 99%

Zebrafish Models for Human Cancer

Shive

2012

Vet Pathol

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For decades, the advancement of cancer research has relied on in vivo models for examining key processes in cancer pathogenesis, including neoplastic transformation, progression, and response to therapy. These studies, which have traditionally relied on rodent models, have engendered a vast body of scientific literature. Recently, experimental cancer researchers have embraced many new and alternative model systems, including the zebrafish (Danio rerio). The general benefits of the zebrafish model for laboratory investigation, such as cost, size, fecundity, and generation time, were quickly superseded by the discovery that zebrafish are amenable to a wide range of investigative techniques, many of which are difficult or impossible to perform in mammalian models. These advantages, coupled with the finding that many aspects of carcinogenesis are conserved in zebrafish as compared with humans, have firmly established a unique niche for the zebrafish model in comparative cancer research. This article introduces methods for generating cancer models in zebrafish and reviews a range of models that have been developed for specific cancer types. Keywords animal disease models, cancer, genetic modification, zebrafishThe zebrafish (Danio rerio) emerged as a model for scientific research in the 1930s, with many early studies devoted to the investigation of developmental processes in embryos. 53 The use of zebrafish in research has subsequently expanded into a broad range of disciplines. As a research species, zebrafish offer certain advantages over traditional vertebrate models, including rapid generation time, high fecundity, external embryonic development, a capacity for high stocking density in relatively small areas, and lower maintenance costs. 64 In recent years, the zebrafish has come into its own as a relevant comparative model for a diverse spectrum of human diseases.Although zebrafish are relative newcomers to the field of comparative cancer research, these small animals have emerged as a powerful tool for investigators. As vertebrate organisms, they share many features of embryonic development and adult anatomy that are critical for comparative animal models. 64,71 In the world of cancer research, this has important implications ranging from conserved signaling pathways and transcriptional regulatory mechanisms, to organogenesis and tissue differentiation, to cellular transformation and tumor initiation. Zebrafish cancer models have been produced by a variety of methods, leading to a broad spectrum of cancer susceptibilities in animals of multiple age groups. Flexibility in genetic manipulation, adaptability to current tools for cancer analysis, and capacity to define cellular and molecular interactions in vivo provide the zebrafish with its own very unique set of advantages for the investigation of cancer biology. Mechanisms for Developing Cancer Models in ZebrafishZebrafish cancer models have been developed by a number of mechanisms (Table 1). Although initial studies relied on chemical carcinogens for t...

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“…Recent comparative genomics analysis of the zebrafish reference genome (Zv9) revealed 26,206 protein-coding genes, with 71% having human orthologues, of which 82% are correlated with diseaseassociated genes in the Online Mendelian Inheritance in Man (OMIM) database 13,14 . Consequently, the zebrafish has been used to model diverse types of human cancers, including neuroblastoma 8 , T-cell acute lymphoblastic leukemia (T-ALL) 15,16 , melanoma 17,18 , Ewing's sarcoma 19 , rhabdomyosarcoma 20,21 , pancreatic carcinoma 22 , hepatocellular carcinoma 23 and myeloid malignancies 24,25 , and has been selected as a cancer model for xenotransplantation studies . To develop such a model ( Figure 1A), one injects a DNA construct containing the gene of interest driven by a tissue-specific promoter into one-cell wild-type embryos.…”

Section: Introductionmentioning

confidence: 99%

Mosaic Zebrafish Transgenesis for Functional Genomic Analysis of Candidate Cooperative Genes in Tumor Pathogenesis

Ung

Guo

Zhu

et al. 2015

JoVE

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Comprehensive genomic analysis has uncovered surprisingly large numbers of genetic alterations in various types of cancers. To robustly and efficiently identify oncogenic "drivers" among these tumors and define their complex relationships with concurrent genetic alterations during tumor pathogenesis remains a daunting task. Recently, zebrafish have emerged as an important animal model for studying human diseases, largely because of their ease of maintenance, high fecundity, obvious advantages for in vivo imaging, high conservation of oncogenes and their molecular pathways, susceptibility to tumorigenesis and, most importantly, the availability of transgenic techniques suitable for use in the fish. Transgenic zebrafish models of cancer have been widely used to dissect oncogenic pathways in diverse tumor types. However, developing a stable transgenic fish model is both tedious and time-consuming, and it is even more difficult and more time-consuming to dissect the cooperation of multiple genes in disease pathogenesis using this approach, which requires the generation of multiple transgenic lines with overexpression of the individual genes of interest followed by complicated breeding of these stable transgenic lines. Hence, use of a mosaic transient transgenic approach in zebrafish offers unique advantages for functional genomic analysis in vivo. Briefly, candidate transgenes can be coinjected into one-cell-stage wild-type or transgenic zebrafish embryos and allowed to integrate together into each somatic cell in a mosaic pattern that leads to mixed genotypes in the same primarily injected animal. This permits one to investigate in a faster and less expensive manner whether and how the candidate genes can collaborate with each other to drive tumorigenesis. By transient overexpression of activated ALK in the transgenic fish overexpressing MYCN, we demonstrate here the cooperation of these two oncogenes in the pathogenesis of a pediatric cancer, neuroblastoma that has resisted most forms of contemporary treatment. Video LinkThe video component of this article can be found at

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A zebrafish transgenic model of Ewing’s sarcoma reveals conserved mediators of EWS-FLI1 tumorigenesis

Cited by 63 publications

References 58 publications

Combined experience of six independent laboratories attempting to create an Ewing sarcoma mouse model

Combined experience of six independent laboratories attempting to create an Ewing sarcoma mouse model

Zebrafish Models for Human Cancer

Mosaic Zebrafish Transgenesis for Functional Genomic Analysis of Candidate Cooperative Genes in Tumor Pathogenesis

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