title: CIC-DUX4Induces Small Round Cell Sarcomas Distinct from Ewing Sarcoma.
abstract: CIC-DUX4sarcoma (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 anex vivomouse model for CDS by transducing embryonic mesenchymal cells (eMC) with humanCIC-DUX4cDNA. Recipient mice transplanted with eMC-expressingCIC-DUX4rapidly 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, andZic1IHC analyses for both mouse and human tumors showed that CCND2 and MUC5AC are reliable biomarkers to distinguish CDS from ES. Gene silencing ofCIC-DUX4as well asCcnd2, Ret, andBcl2effectively inhibited CDS tumor growthin vitroThe 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.Cancer Res; 77(11); 2927-37. ©2017 AACR.
authors.affiliation: Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.|Department of Pathology, Toranomon Hospital, Tokyo Japan.
authors.forename: Toyoki
authors.initials: T
authors.lastname: Yoshimoto
authors.affiliation: Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Miwa
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Homme
authors.affiliation: Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Yamazaki
authors.affiliation: Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Takazawa
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
authors.affiliation: Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan. takuro-ind@umin.net.
authors.forename: Takuro
authors.initials: T
authors.lastname: Nakamura
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics*; D001859:Bone Neoplasms / Q000235:genetics*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D046228:Microarray Analysis; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D012512:Sarcoma, Ewing / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C574694:CIC-DUX4 fusion protein, human; D015514:Oncogene Proteins, Fusion