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Modeling the initiation of Ewing sarcoma tumorigenesis in differentiating human embryonic stem cells

Oncogene volume 35, pages 3092–3102 (2016)Cite this article

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Abstract

Oncogenic transformation in Ewing sarcoma tumors is driven by the fusion oncogene EWS-FLI1. However, despite the well-established role of EWS-FLI1 in tumor initiation, the development of models of Ewing sarcoma in human cells with defined genetic elements has been challenging. Here, we report a novel approach to model the initiation of Ewing sarcoma tumorigenesis that exploits the developmental and pluripotent potential of human embryonic stem cells. The inducible expression of EWS-FLI1 in embryoid bodies, or collections of differentiating stem cells, generates cells with properties of Ewing sarcoma tumors, including characteristics of transformation. These cell lines exhibit anchorage-independent growth, a lack of contact inhibition and a strong Ewing sarcoma gene expression signature. Furthermore, these cells also demonstrate a requirement for the persistent expression of EWS-FLI1 for cell survival and growth, which is a hallmark of Ewing sarcoma tumors.

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Acknowledgements

We thank Hubo Li for helpful discussions and Kelli Goss for assistance with the drug dose-response experiments. DJG is supported by a NCI K08 award (5K08 CA160346-03), a CureSearch Award and a Sarcoma Foundation of America Award. DP is a HHMI investigator and supported by NIH grant GM083299.

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Author notes

  1. D J Gordon

    Present address: 4Current address: Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of Iowa, Iowa City, IA, USA.,

  2. M Motwani

    Present address: 5Current address: Graduate School of Biomedical Sciences, University of Massachusetts Medical School, Worcester, MA 01655, USA.,

Authors and Affiliations

  1. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    D J Gordon, M Motwani & D Pellman

  2. Department of Cell Biology, Harvard Medical School, Boston, MA, USA

    D Pellman

  3. Howard Hughes Medical Institute, Boston, MA, USA

    D Pellman

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Correspondence to D J Gordon or D Pellman.

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Gordon, D., Motwani, M. & Pellman, D. Modeling the initiation of Ewing sarcoma tumorigenesis in differentiating human embryonic stem cells. Oncogene 35, 3092–3102 (2016). https://doi.org/10.1038/onc.2015.368

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