Targeting the Wnt pathway in synovial sarcoma models

Whitney Barham, Andrea L. Frump, Taylor P. Sherrill, Christina B. Garcia, Kenyi Saito-Diaz, Michael Vansaun, Barbara Fingleton, Linda Gleaves, Darren Orton, Mario R. Capecchi, Timothy S. Blackwell, Ethan Lee, Fiona Yull, Josiane E. Eid

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Synovial sarcoma is an aggressive soft-tissue malignancy of children and young adults, with no effective systemic therapies. Its specific oncogene, SYT-SSX (SS18-SSX), drives sarcoma initiation and development. The exact mechanism of SYT-SSX oncogenic function remains unknown. In an SYT-SSX2 transgenic model, we show that a constitutive Wnt/β-catenin signal is aberrantly activated by SYT-SSX2, and inhibition of Wnt signaling through the genetic loss of β-catenin blocks synovial sarcoma tumor formation. In a combination of cell-based and synovial sarcoma tumor xenograft models, we show that inhibition of the Wnt cascade through coreceptor blockade and the use of small-molecule CK1α activators arrests synovial sarcoma tumor growth. We find that upregulation of the Wnt/β-catenin cascade by SYT-SSX2 correlates with its nuclear reprogramming function. These studies reveal the central role of Wnt/β-catenin signaling in SYT-SSX2-induced sarcoma genesis, and open new venues for the development of effective synovial sarcoma curative agents. SIGNIFICANCE: Synovial sarcoma is an aggressive soft-tissue cancer that afflicts children and young adults, and for which there is no effective treatment. The current studies provide critical insight into our understanding of the pathogenesis of SYT-SSX-dependent synovial sarcoma and pave the way for the development of effective therapeutic agents for the treatment of the disease in humans.

Original languageEnglish (US)
Pages (from-to)1286-1301
Number of pages16
JournalCancer Discovery
Volume3
Issue number11
DOIs
StatePublished - Nov 2013
Externally publishedYes

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Synovial Sarcoma
Wnt Signaling Pathway
Catenins
Neoplasms
Sarcoma
Young Adult
Therapeutics
Oncogenes
Heterografts
Up-Regulation
SYT-SSX fusion protein
Growth

ASJC Scopus subject areas

  • Oncology

Cite this

Barham, W., Frump, A. L., Sherrill, T. P., Garcia, C. B., Saito-Diaz, K., Vansaun, M., ... Eid, J. E. (2013). Targeting the Wnt pathway in synovial sarcoma models. Cancer Discovery, 3(11), 1286-1301. https://doi.org/10.1158/2159-8290.CD-13-0138

Targeting the Wnt pathway in synovial sarcoma models. / Barham, Whitney; Frump, Andrea L.; Sherrill, Taylor P.; Garcia, Christina B.; Saito-Diaz, Kenyi; Vansaun, Michael; Fingleton, Barbara; Gleaves, Linda; Orton, Darren; Capecchi, Mario R.; Blackwell, Timothy S.; Lee, Ethan; Yull, Fiona; Eid, Josiane E.

In: Cancer Discovery, Vol. 3, No. 11, 11.2013, p. 1286-1301.

Research output: Contribution to journalArticle

Barham, W, Frump, AL, Sherrill, TP, Garcia, CB, Saito-Diaz, K, Vansaun, M, Fingleton, B, Gleaves, L, Orton, D, Capecchi, MR, Blackwell, TS, Lee, E, Yull, F & Eid, JE 2013, 'Targeting the Wnt pathway in synovial sarcoma models', Cancer Discovery, vol. 3, no. 11, pp. 1286-1301. https://doi.org/10.1158/2159-8290.CD-13-0138
Barham W, Frump AL, Sherrill TP, Garcia CB, Saito-Diaz K, Vansaun M et al. Targeting the Wnt pathway in synovial sarcoma models. Cancer Discovery. 2013 Nov;3(11):1286-1301. https://doi.org/10.1158/2159-8290.CD-13-0138
Barham, Whitney ; Frump, Andrea L. ; Sherrill, Taylor P. ; Garcia, Christina B. ; Saito-Diaz, Kenyi ; Vansaun, Michael ; Fingleton, Barbara ; Gleaves, Linda ; Orton, Darren ; Capecchi, Mario R. ; Blackwell, Timothy S. ; Lee, Ethan ; Yull, Fiona ; Eid, Josiane E. / Targeting the Wnt pathway in synovial sarcoma models. In: Cancer Discovery. 2013 ; Vol. 3, No. 11. pp. 1286-1301.
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