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

Jared J. Barrott; Benjamin E. Illum; Huifeng Jin; Ju-Fen Zhu; Tim Mosbruger; Michael J. Monument; Kyllie Smith-Fry; Matthew G. Cable; Yanliang Wang; Allie H. Grossmann; Mario R. Capecchi; Kevin B. Jones

doi:10.18632/oncotarget.4283

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Research Papers:

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

Jared J. Barrott _, Benjamin E. Illum, Huifeng Jin, Ju-Fen Zhu, Tim Mosbruger, Michael J. Monument, Kyllie Smith-Fry, Matthew G. Cable, Yanliang Wang, Allie H. Grossmann, Mario R. Capecchi and Kevin B. Jones

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Oncotarget. 2015; 6:22758-22766. https://doi.org/10.18632/oncotarget.4283

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Abstract

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

Correspondence to:

Kevin B. Jones, e-mail: [email protected]

Keywords: epithelial-mesenchymal transition, translocation, Wnt-signaling, mouse genetic model

Received: April 24, 2015 Accepted: May 26, 2015 Published: June 08, 2015

ABSTRACT

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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Research Papers:

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

Abstract