Fiona Yull

Last active: 3/21/2018

Targeting the Wnt pathway in synovial sarcoma models.

Barham W, Frump AL, Sherrill TP, Garcia CB, Saito-Diaz K, VanSaun MN, Fingleton B, Gleaves L, Orton D, Capecchi MR, Blackwell TS, Lee E, Yull F, Eid JE
Cancer Discov. 2013 3 (11): 1286-301

PMID: 23921231 · PMCID: PMC3823757 · DOI:10.1158/2159-8290.CD-13-0138

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.

©2013 AACR.

MeSH Terms (17)

Adolescent Adult Animals Cell Line, Tumor Gene Expression Regulation, Neoplastic Gene Knockout Techniques Humans Mice Mice, Nude Mice, Transgenic Oncogene Proteins, Fusion Pyrvinium Compounds Sarcoma, Experimental Sarcoma, Synovial Wnt Signaling Pathway Xenograft Model Antitumor Assays Young Adult

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