Universiteit Leiden

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Research project

Zebrafish: a new engraft model to study Ewing sarcoma progression

Can zebrafish provide a fast, sensitive in vivo vertebrate model for identifying novel mechanisms of Ewing sarcoma progression and for development of new anticancer compounds in a time- and cost-effective manner?

Duration
2009  -   2013
Contact
Ewa Snaar-Jagalska
Funding
KiKa Foundation (Stichting Kinderenkankervrij) KiKa Foundation (Stichting Kinderenkankervrij)
Partners

Prof. PCW Hogendoorn, Pathology, Leiden University Medical Center, Leiden, the Netherlands

 

 

Ewing sarcoma is a bone- and soft tissue tumour with a poor prognosis for patients with metastases and/or recurring disease. Although the genetic abnormality causing Ewing sarcoma is known, no reliable therapies have been found yet. There is a clear need to develop more sophisticated bioassays/drug screens that go beyond the in vitro use of classical cancer cell lines and in vivo mouse xeno-transplantation studies, and allow medium to high-throughput application within an animal in preclinical target discovery and drug lead identification.

Ewing sarcoma (ES) is a malignant bone tumour most commonly found in children and young adults. The current treatment strategy in case of localized tumours results in a survival rate of 60-65%. In case of primary metastases the 5-year event free survival is only 20%. At the time of diagnosis, metastases are present in approximately 25% of the cases.

Zebrafish models have the benefit that there is a high conservation of (proto-) oncogenes and tumour suppressor genes between zebrafish and human, making the zebrafish model ideal for identifying clinically relevant genes and compounds. In addition, zebrafish form tumours with similar histopathological and gene profiling features as human tumours; xenotransplantation with human tumour cells is therefore possible. For other tumour types, it has been shown that various hallmarks of cancer (such as proliferation, migration and induction of angiogenesis) can be observed within one week after implantation.

Furthermore, zebrafish can readily take up chemical compounds from the water they are kept in, making them very suitable for drug- and lead compound screenings. The goal of this project is to optimize the zebrafish as a Ewing sarcoma cancer model, study the host response to cancer cell implantation, determine which genes play a key role in ES malignancy and determine targets for gene therapy and drugs. This project aiming for two highly inter-related objectives: Discovery of genetic targets and novel lead compounds that control specific aspects of ES progression using shRNA interference and chemical screens.

  • Tulotta C, He S, Chen L, Groenewoud A, van der Ent W, Meijer AH, Spaink HP, Snaar-Jagalska BE (2016) Imaging of Human Cancer Cell Proliferation, Invasion, and Micrometastasis in a Zebrafish Xenogeneic Engraftment Model. Methods Mol Biol. 2016;1451:155-69. doi: 10.1007/978-1-4939-3771-4_11.
  • van der Ent W, Veneman WJ, Groenewoud A, Chen L, Tulotta C, Hogendoorn PC, Spaink HP, Snaar-Jagalska BE (2016) Automation of Technology for Cancer Research. Adv Exp Med Biol. 2016;916:315-32. doi: 10.1007/978-3-319-30654-4_14. Review.
  • Kovar H, Amatruda J, Brunet E, Burdach S, Cidre-Aranaz F, de Alava E, Dirksen U, van der Ent W, Grohar P, Grünewald TG, Helman L, Houghton P, Iljin K, Korsching E, Ladanyi M, Lawlor E, Lessnick S, Ludwig J, Meltzer P, Metzler M, Mora J, Moriggl R, Nakamura T, Papamarkou T, Radic Sarikas B, Rédini F, Richter GH, Rossig C, Schadler K, Schäfer BW, Scotlandi K, Sheffield NC, Shelat A, Snaar-Jagalska BE, Sorensen P, Stegmaier K, Stewart E, Sweet-Cordero A, Szuhai K, Tirado OM, Tirode F, Toretsky J, Tsafou K, Üren A, Zinovyev A, Delattre O (2016) The second European interdisciplinary Ewing sarcoma research summit - A joint effort to deconstructing the multiple layers of a complex disease. Oncotarget 7:8613-24.
  • Franzetti GA, Laud-Duval K, Van Der Ent W, Brisac A, Irondelle M, Aubert S, Dirksen U, Bouvier C, de Pinieux G, Snaar-Jagalska BE, Chavrier P and Delattre O (2016) Cell-to-cell heterogeneity of EWSR1-FLI1 expression level determines proliferation/migration choices in Ewing sarcoma cells. Oncogene.
  • Van der Ent W, Jochemsen AG, Teunisse AF, Krens FG, Szuhai K, Spaink HP, Hogendoorn PCW, Snaar-Jagalska BE (2014) Ewing sarcoma inhibition by disruption of EWSR1-FLI1 transcriptional activity and reactivation of p53. J. Pathology, 233(4): 415-24.
  • Ban J, Aryee DN, Fourtouna A, van der Ent W, Kauer M, Niedan S, Machado I, Rodriguez-Galindo C, Tirado OM, Schwentner R, Picci P, Flanagan AM, Berg V, Strauss SJ, Scotlandi K, Lawlor ER, Snaar-Jagalska BE, Llombart-Bosch A, Kovar H (2014) Suppression of deacetylase SIRT1 mediates tumor-suppressive NOTCH response and offers a novel treatment option in metastatic Ewing sarcoma. Cancer Res. 74(22): 6578-88. 

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