96 <strong>EURON</strong> <strong>and</strong> <strong>THEME</strong> <strong>joint</strong> <strong>meeting</strong> 2011 Inhibition of WNT signaling impairs growth of synovial sarcoma cells M. Trautmann 1 , E. Sievers 1 , D. Kindler 1 , A. Koch 3 , R. Büttner 2 , W. Hartmann 1 1 Institute of Pathology, University Hospital Bonn, Sigmund-Freud Str. 25, 53127 Bonn, Germany; 2 Institute of Pathology, University Hospital Cologne, Kerpener Str. 62, 50924 Cologne, Germany; 3 Department of Neuropathology, Charité Universitätsmedizin, Charitéplatz 1,10117 Berlin, Germany. Synovial sarcoma is a rare malignant soft tissue tumor affecting mainly adolescents <strong>and</strong> young adults. The hallmark of synovial sarcoma is the presence of a reciprocal balanced t(X;18) translocation, leading to the fusion of the SS18 gene to either the SSX1, SSX2 or rarely the SSX4 gene, resulting in a chimeric transcriptional modifier. Therapeutic outcome of synovial sarcomas is primarily determined by the efficiency of surgery as a high tendency for local relapse is documented. St<strong>and</strong>ardized chemo-<strong>and</strong> radiotherapy are further therapeutic options, however, specific targeted therapies are currently not available. Recently, several expression profiling studies in mesenchymal malignancies revealed gene expression signatures indicating WNT signaling activation in synovial sarcomas. This study was performed to examine the functional relevance of WNT signaling in synovial sarcomas <strong>and</strong> to evaluate if interference with the WNT signaling pathway might represent an option in the development of novel <strong>and</strong> highly selective drugs in the treatment of synovial sarcoma. To assess the prevalence of WNT signaling activation in a set of 30 synovial sarcoma tumor samples, nuclear staining of β-catenin was analyzed immunohistochemically. Nuclear β-catenin signals were observed in a significant subset of these tumors, indicating activation of the WNT signaling pathway. In order to evaluate whether WNT activation is molecularly dependent on the SS18/SSX fusion proteins, tetracycline-inducible systems overexpressing the SS18/SSX fusion proteins were established in T-Rex293 cells. In luciferase reporter assays employing the TOP-/FOPflash system, expression of SS18/SSX proteins effectively activated TCF/β-catenin mediated transcriptional activity, which was associated with nuclear recruitment of β-catenin. Five human synovial sarcoma cell lines were subsequently treated with small molecular inhibitors of WNT signaling. In MTT assays, a significant dose-dependent inhibition of cellular growth were observed, which was accompanied by decreased expression of the WNT downstream targets c-Myc <strong>and</strong> Cyclin D1. In flow cytometric analyses, the growth effects exerted by the inhibitors were shown to be due to a reduction of cellular proliferation combined with an increase of apoptosis. In summary, our data emphasize the pivotal role of WNT signaling in synovial
97 <strong>EURON</strong> <strong>and</strong> <strong>THEME</strong> <strong>joint</strong> <strong>meeting</strong> 2011 sarcoma <strong>and</strong> indicate its functional dependence on the characteristic SS18/SSX translocation. Furthermore, our study demonstrates that targeting the WNT signaling pathway provides a specific, molecularly founded therapeutic strategy in the treatment of synovial sarcoma. Additional functional studies in vitro <strong>and</strong> in vivo are required to further underst<strong>and</strong> the role of WNT signaling <strong>and</strong> its therapeutic applicability in synovial sarcomas.
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