title: β-catenin stabilization enhances SS18-SSX2-driven synovial sarcomagenesis and blocks the mesenchymal to epithelial transition.
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.
authors.affiliation: Department of Orthopaedics and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Jared J
authors.initials: JJ
authors.lastname: Barrott
authors.affiliation: Department of Orthopaedics and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Illum
authors.affiliation: Department of Orthopaedics and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Huifeng
authors.initials: H
authors.lastname: Jin
authors.affiliation: Department of Orthopaedics and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Ju-Fen
authors.initials: JF
authors.lastname: Zhu
authors.affiliation: Department of Bioinformatics and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Mosbruger
authors.affiliation: Department of Orthopaedics and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Monument
authors.affiliation: Department of Orthopaedics and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Kyllie
authors.initials: K
authors.lastname: Smith-Fry
authors.affiliation: Department of Orthopaedics and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Cable
authors.affiliation: Department of Orthopaedics and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Yanliang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathology and ARUP Laboratories, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Allie H
authors.initials: AH
authors.lastname: Grossmann
authors.affiliation: Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Mario R
authors.initials: MR
authors.lastname: Capecchi
authors.affiliation: Department of Orthopaedics and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Jones
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D013584:Sarcoma, Synovial / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015533:Transcriptional Activation; D014162:Transfection; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D015514:Oncogene Proteins, Fusion; C116512:SYT-SSX fusion protein; D051176:beta Catenin
keywords: Wnt-signaling; epithelial-mesenchymal transition; mouse genetic model; translocation