Targeting the Wnt pathway in synovial sarcoma models

Whitney Barham, Andrea L. Frump, Taylor P. Sherrill, Christina B. Garcia, Kenyi Saito-Diaz, Michael N. 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

41 Scopus citations

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

ASJC Scopus subject areas

  • Oncology

Fingerprint Dive into the research topics of 'Targeting the Wnt pathway in synovial sarcoma models'. Together they form a unique fingerprint.

  • Cite this

    Barham, W., Frump, A. L., Sherrill, T. P., Garcia, C. B., Saito-Diaz, K., VanSaun, M. N., Fingleton, B., Gleaves, L., Orton, D., Capecchi, M. R., Blackwell, T. S., Lee, E., Yull, F., & 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