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

// Tsion Zewdu Minas 1,* , Didier Surdez 2,3,* , Tahereh Javaheri 4,* , Miwa Tanaka 5,* , Michelle Howarth 6,* , Hong-Jun Kang 7,* , Jenny Han 1 , Zhi-Yan Han 2,3 , Barbara Sax 4 , Barbara E. Kream 8 , Sung-Hyeok Hong 1 , Haydar Çelik 1 , Franck Tirode 2,3 , Jan Tuckermann 9 , Jeffrey A. Toretsky 1 , Lukas Kenner 4,10,15 , Heinrich Kovar 12,13 , Sean Lee 7 , E. Alejandro Sweet-Cordero 6 , Takuro Nakamura 5 , Richard Moriggl 4,11,16 , Olivier Delattre 2,3,14 and Aykut Üren 1 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.