<i>CIC-DUX4</i> Induces Small Round Cell Sarcomas Distinct from Ewing Sarcoma.

Abstract

<i>CIC-DUX4</i> sarcoma (CDS) or CIC-rearranged sarcoma is a subcategory of small round cell sarcoma resembling the morphological phenotypes of Ewing sarcoma (ES). However, 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 <i>ex vivo</i> mouse model for CDS by transducing embryonic mesenchymal cells (eMC) with human <i>CIC-DUX4</i> cDNA. Recipient mice transplanted with eMC-expressing <i>CIC-DUX4</i> 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, <i>Ccnd2, Crh</i>, and <i>Zic1</i> IHC analyses for both mouse and human tumors showed that CCND2 and MUC5AC are reliable biomarkers to distinguish CDS from ES. Gene silencing of <i>CIC-DUX4</i> as well as <i>Ccnd2, Ret</i>, and <i>Bcl2</i> effectively inhibited CDS tumor growth <i>in vitro</i> 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. <i>Cancer Res; 77(11); 2927-37. ©2017 AACR</i>.