Targeting the Wnt pathway in synovial sarcoma models

• Published in: Cancer discovery 2013-11, Vol.3 (11), p.1286-1301
• Main Authors: Barham, Whitney, Frump, Andrea L, Sherrill, Taylor P, Garcia, Christina B, Saito-Diaz, Kenyi, VanSaun, Michael N, Fingleton, Barbara, Gleaves, Linda, Orton, Darren, Capecchi, Mario R, Blackwell, Timothy S, Lee, Ethan, Yull, Fiona, Eid, Josiane E
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Animals; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Gene Knockout Techniques; Humans; Mice; Mice, Nude; Mice, Transgenic; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Pyrvinium Compounds - pharmacology; Sarcoma, Experimental; Sarcoma, Synovial - genetics; Sarcoma, Synovial - metabolism; Sarcoma, Synovial - pathology; Wnt Signaling Pathway - drug effects; Xenograft Model Antitumor Assays; Young Adult
• ISSN: 2159-8274; 2159-8290
• DOI: 10.1158/2159-8290.cd-13-0138

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. 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.