β-catenin stabilization enhances SS18-SSX2-driven synovial sarcomagenesis and blocks the mesenchymal to epithelial transition
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Jared J. Barrott1,*, Benjamin E. Illum1,*, Huifeng Jin1, Ju-Fen Zhu1, Tim Mosbruger2, Michael J. Monument1, Kyllie Smith-Fry1, Matthew G. Cable1, Yanliang Wang1, Allie H. Grossmann3, Mario R. Capecchi4, Kevin B. Jones1
1Department of Orthopaedics and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
2Department of Bioinformatics and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
3Department of Pathology and ARUP Laboratories, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
4Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
*These authors have contributed equally to this work
Kevin B. Jones, e-mail: firstname.lastname@example.org
Keywords: epithelial-mesenchymal transition, translocation, Wnt-signaling, mouse genetic model
Received: April 24, 2015 Accepted: May 26, 2015 Published: June 08, 2015
β-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 β-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 β-catenin greatly enhances synovial sarcomagenesis. Stabilization of β-catenin enables a stem-cell phenotype in synovial sarcoma cells, specifically blocking epithelial differentiation and driving invasion. β-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 β-catenin’s transcriptional contribution includes blocking epithelial differentiation.
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