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Targeting the Wnt pathway in synovial sarcoma models.


Barham WWhitney , Frump AL Andrea L , Sherrill TP Taylor P , Garcia CB Christina B , Saito-Diaz K Kenyi , VanSaun MN Michael N , Fingleton B Barbara , Gleaves L Linda , Orton D Darren , Capecchi MR Mario R , Blackwell TS Timothy S , Lee E Ethan , Yull F Fiona , Eid JE Josiane E . Cancer Discovery. 2013 11 ; 3(11). 1286-301


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.