Oncotarget

Research Papers:

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

Tsion Zewdu Minas, Didier Surdez, Tahereh Javaheri, Miwa Tanaka, Michelle Howarth, Hong-Jun Kang, Jenny Han, Zhi-Yan Han, Barbara Sax, Barbara E. Kream, Sung-Hyeok Hong, Haydar Çelik, Franck Tirode, Jan Tuckermann, Jeffrey A. Toretsky, Lukas Kenner, Heinrich Kovar, Sean Lee, E. Alejandro Sweet-Cordero, Takuro Nakamura, Richard Moriggl, Olivier Delattre and Aykut Üren _

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Oncotarget. 2017; 8:34141-34163. https://doi.org/10.18632/oncotarget.9388

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Abstract

Tsion Zewdu Minas1,*, Didier Surdez2,3,*, Tahereh Javaheri4,*, Miwa Tanaka5,*, Michelle Howarth6,*, Hong-Jun Kang7,*, Jenny Han1, Zhi-Yan Han2,3, Barbara Sax4, Barbara E. Kream8, Sung-Hyeok Hong1, Haydar Çelik1, Franck Tirode2,3, Jan Tuckermann9, Jeffrey A. Toretsky1, Lukas Kenner4,10,15, Heinrich Kovar12,13, Sean Lee7, E. Alejandro Sweet-Cordero6, Takuro Nakamura5, Richard Moriggl4,11,16, Olivier Delattre2,3,14 and Aykut Üren1

1 Department of Oncology, Georgetown University Medical Center, Washington, DC, United States of America

2 Genetics and Biology of Cancers Unit, Institut Curie Research Center, PSL Research University, Île-de-France, Paris, France

3 INSERM U830, Institut Curie Research Center, Île-de-France, Paris, France

4 Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria

5 Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan

6 Division of Hematology and Oncology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States of America

7 Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, United States of America

8 Department of Medicine, and Genetics and Genome Sciences, University of Connecticut Health Science Center, Farmington, CT, United States of America

9 Institute of Comparative Molecular Endocrinology (CME), University of Ulm, Ulm, Germany

10 Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria

11 Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria

12 Department of Pediatrics, Medical University of Vienna, Vienna, Austria

13 Children´s Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria

14 Unité de génétique somatique, Institut Curie, Île-de-France, Paris, France

15 Department of Pathology of Laboratory Animals (UPLA), University of Veterinary Medicine, Vienna, Austria

16 Medical University of Vienna, Vienna, Austria

* These authors have contributed equally to this work

Correspondence to:

Aykut Üren, email:

Sean Lee, email:

E. Alejandro Sweet-Cordero, email:

Takuro Nakamura, email:

Richard Moriggl, email:

Olivier Delattre, email:

Keywords: Ewing sarcoma, EWS-FLI1, EWS-FLI1 driven transgenic mouse model

Received: November 09, 2015 Accepted: May 05, 2016 Published: May 15, 2016

Abstract

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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