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

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

doi:10.18632/oncotarget.9388

Cited by 79 publications

(86 citation statements)

References 99 publications

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“…CIC-DUX4 gene fusion is the initiating and causative event in CDS, encoding a chimeric transcription factor consisting of the large part of CIC including its DNA-binding HMG box, and the transcriptional activation domain derived from the DUX4 C-terminus (2). Deregulation of CIC target genes such as ETV4 is one of the key events in the development and progression of CDS (2), and chimeric transcription factors act as an oncogene only in proper cellular context (7-9). We have previously successfully generated an Ewing sarcoma mouse model utilizing an ex vivo -based technology (7).…”

Section: Introductionmentioning

confidence: 99%

CIC-DUX4 Induces Small Round Cell Sarcomas Distinct from Ewing Sarcoma

et al. 2017

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CIC-DUX4 sarcoma (CDS) or CIC-rearranged sarcoma is a subcategory of small round cell sarcoma resembling the morphological phenotypes of Ewing sarcoma (ES). Hoever, recent clinicopathologic and molecular genetic analyses indicate that CDS is an independent disease entity from ES. Few ancillary markers have been used in the differential diagnosis of CDS, and additional CDS-specific biomarkers are needed for more definitive classification. Here we report the generation of an ex vivo mouse model for CDS by transducing embryonic mesenchymal cells (eMC) with human CIC-DUX4 cDNA. Recipient mice transplanted with eMC expressing CIC-DUX4 rapidly developed an aggressive, undifferentiated sarcoma composed of small-round to short-spindle cells. Gene expression profiles of CDS and eMC revealed upregulation of CIC-DUX4 downstream genes such as PEA3 family genes, Ccnd2, Crh and Zic1. Immunohistochemical analyses for both mouse and human tumors showed that CCND2 and MUC5AC are reliable biomarkers to distinguish CDS from ES. Gene silencing of CIC-DUX4 as well as Ccnd2, Ret, and Bcl2 effectively inhibited CDS tumor growth in vitro. The CDK4/6 inhibitor palbociclib and the soft tissue sarcoma drug trabectedin also blocked the growth of mouse CDS. In summary, our mouse model provides important biological information about CDS and provides a useful platform to explore biomarkers and therapeutic agents for CDS.

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Section: Introductionmentioning

confidence: 99%

CIC-DUX4 Induces Small Round Cell Sarcomas Distinct from Ewing Sarcoma

et al. 2017

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“…This finding is in agreement with recent studies of Ewing sarcoma suggesting that MSCs might not represent the target cell-for-transformation in Ewing sarcoma (Kovar et al., 2016, Minas et al., 2016, Renouf et al., 2014, Rodriguez et al., 2011). We therefore attempted to induce the t(11;22) translocation in a less differentiated cell type.…”

Section: Discussionmentioning

confidence: 99%

Efficient Recreation of t(11;22) EWSR1-FLI1+ in Human Stem Cells Using CRISPR/Cas9

et al. 2017

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SummaryEfficient methodologies for recreating cancer-associated chromosome translocations are in high demand as tools for investigating how such events initiate cancer. The CRISPR/Cas9 system has been used to reconstruct the genetics of these complex rearrangements at native loci while maintaining the architecture and regulatory elements. However, the CRISPR system remains inefficient in human stem cells. Here, we compared three strategies aimed at enhancing the efficiency of the CRISPR-mediated t(11;22) translocation in human stem cells, including mesenchymal and induced pluripotent stem cells: (1) using end-joining DNA processing factors involved in repair mechanisms, or (2) ssODNs to guide the ligation of the double-strand break ends generated by CRISPR/Cas9; and (3) all-in-one plasmid or ribonucleoprotein complex-based approaches. We report that the generation of targeted t(11;22) is significantly increased by using a combination of ribonucleoprotein complexes and ssODNs. The CRISPR/Cas9-mediated generation of targeted t(11;22) in human stem cells opens up new avenues in modeling Ewing sarcoma.

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“…However, development of transgenic mouse-models is hampered by toxicity of EWSR1-FLI1 to most cells [33] . Additional genetic variations may be needed to create a permissive environment, implied by the bias of disease occurrence in Caucasians [1] .…”

Section: Chromosomal Translocationsmentioning

confidence: 99%

“…However, despite many attempts made, no research group as of yet has been successful [33] . Introduction of the EWS oncogene EWSR1-FLI1 in mice has led to embryonic lethality, or development of non-EWS-resembling cancer [84,85] .…”

Section: Model Systemsmentioning

confidence: 99%

“…Introduction of the EWS oncogene EWSR1-FLI1 in mice has led to embryonic lethality, or development of non-EWS-resembling cancer [84,85] . For a comprehensive overview of the efforts made by six independent laboratories to generate a murine model for EWS, we refer to the 2016 publication by Minas et al [33] . In addition to murine models, development of zebrafish transgenic models for EWS has also been attempted.…”

Section: Model Systemsmentioning

confidence: 99%

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Molecular genetics of Ewing sarcoma, model systems and finding novel (immuno-) therapeutic targets

Ent¹,

Sand²,

Hogendoorn³

2018

JTGG

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Ewing sarcoma (EWS) is a bone-and soft tissue tumour affecting primarily children and young adults. A quarter of patients present with metastases at the time of diagnosis and have a poor outlook in terms of overall survival. Efforts are made across the field to gain deeper insight in the genetics of this enigmatic neoplasm. EWS is characterized by presence of an oncogenic translocation gene, EWSR1-ETS. In addition, there are a limited number of known recurrent DNA copy number variations and mutations. Subsequent of the above, the epigenetic profile of EWS is subject of interest. In this review, we summarize the current available knowledge on the genetics underpinning EWS, explore the current knowledge of its epigenetic profile, discuss in vitro and in vivo model systems, and explore the unravelling knowledge of potential targets for treatment including recent insights into potential immunotherapy.

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

Cited by 79 publications

References 99 publications

CIC-DUX4 Induces Small Round Cell Sarcomas Distinct from Ewing Sarcoma

CIC-DUX4 Induces Small Round Cell Sarcomas Distinct from Ewing Sarcoma

Efficient Recreation of t(11;22) EWSR1-FLI1+ in Human Stem Cells Using CRISPR/Cas9

Molecular genetics of Ewing sarcoma, model systems and finding novel (immuno-) therapeutic targets

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