Targeting the Wnt pathway in synovial sarcoma models.

Abstract

UNLABELLED:

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.

• Authors: 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
• Journal: Cancer discovery (Cancer Discov) Vol. 3 Issue 11 Pg. 1286-301 (Nov 2013) ISSN: 2159-8290 [Electronic] United States
• PMID: 23921231 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2013 AACR.

Chemical References

• Oncogene Proteins, Fusion
• Pyrvinium Compounds
• SYT-SSX fusion protein
• pyrvinium

Topics

• Adolescent
• Adult
• Animals
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic
• Gene Knockout Techniques
• Humans
• Mice
• Mice, Nude
• Mice, Transgenic
• Oncogene Proteins, Fusion (genetics, metabolism)
• Pyrvinium Compounds (pharmacology)
• Sarcoma, Experimental
• Sarcoma, Synovial (genetics, metabolism, pathology)
• Wnt Signaling Pathway (drug effects)
• Xenograft Model Antitumor Assays
• Young Adult