β-catenin stabilization enhances<i>SS18-SSX2</i>-driven synovial sarcomagenesis and blocks the mesenchymal to epithelial transition

Abstract

// Jared J. Barrott 1, * , Benjamin E. Illum 1, * , Huifeng Jin 1 , Ju-Fen Zhu 1 , Tim Mosbruger 2 , Michael J. Monument 1 , Kyllie Smith-Fry 1 , Matthew G. Cable 1 , Yanliang Wang 1 , Allie H. Grossmann 3 , Mario R. Capecchi 4 , Kevin B. Jones 1 1 Department of Orthopaedics and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA 2 Department of Bioinformatics and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA 3 Department of Pathology and ARUP Laboratories, University of Utah School of Medicine, Salt Lake City, UT 84112, USA 4 Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA * These authors have contributed equally to this work Correspondence to: Kevin B. Jones, e-mail: kevin.jones@hci.utah.edu Keywords: epithelial-mesenchymal transition, translocation, Wnt-signaling, mouse genetic model Received: April 24, 2015&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: May 26, 2015&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: June 08, 2015 ABSTRACT &beta;-catenin is a master regulator in the cellular biology of development and neoplasia. Its dysregulation is implicated as a driver of colorectal carcinogenesis and the epithelial-mesenchymal transition in other cancers. Nuclear &beta;-catenin staining is a poor prognostic sign in synovial sarcoma, the most common soft-tissue sarcoma in adolescents and young adults. We show through genetic experiments in a mouse model that expression of a stabilized form of &beta;-catenin greatly enhances synovial sarcomagenesis. Stabilization of &beta;-catenin enables a stem-cell phenotype in synovial sarcoma cells, specifically blocking epithelial differentiation and driving invasion. &beta;-catenin achieves its reprogramming in part by upregulating transcription of TCF/LEF target genes. Even though synovial sarcoma is primarily a mesenchymal neoplasm, its progression towards a more aggressive and invasive phenotype parallels the epithelial-mesenchymal transition observed in epithelial cancers, where &beta;-catenin&rsquo;s transcriptional contribution includes blocking epithelial differentiation.