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SS18-SSX fusion protein-induced Wnt/β-catenin signaling is a therapeutic target in synovial sarcoma

Oncogene volume 33, pages 5006–5016 (2014)Cite this article

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Abstract

Synovial sarcoma is a high-grade soft tissue malignancy characterized by a specific reciprocal translocation t(X;18), which leads to the fusion of the SS18 (SYT) gene to one of three SSX genes (SSX1, SSX2 or SSX4). The resulting chimeric SS18-SSX protein is suggested to act as an oncogenic transcriptional regulator. Despite multimodal therapeutic approaches, metastatic disease is often lethal and the development of novel targeted therapeutic strategies is required. Several expression-profiling studies identified distinct gene expression signatures, implying a consistent role of Wnt/β-catenin signaling in synovial sarcoma tumorigenesis. Here we investigate the functional and therapeutic relevance of Wnt/β-catenin pathway activation in vitro and in vivo. Immunohistochemical analyses of nuclear β-catenin and Wnt downstream targets revealed activation of canonical Wnt signaling in a significant subset of 30 primary synovial sarcoma specimens. Functional aspects of Wnt signaling including dependence of Tcf/β-catenin complex activity on the SS18-SSX fusion proteins were analyzed. Efficient SS18-SSX-dependent activation of the Tcf/β-catenin transcriptional complex was confirmed by TOPflash reporter luciferase assays and immunoblotting. In five human synovial sarcoma cell lines, inhibition of the Tcf/β-catenin protein–protein interaction significantly blocked the canonical Wnt/β-catenin signaling cascade, accompanied by the effective downregulation of Wnt targets (AXIN2, CDC25A, c-MYC, DKK1, CyclinD1 and Survivin) and the specific suppression of cell viability associated with the induction of apoptosis. In SYO-1 synovial sarcoma xenografts, administration of small molecule Tcf/β-catenin complex inhibitors significantly reduced tumor growth, associated with diminished AXIN2 protein levels. In summary, SS18-SSX-induced Wnt/β-catenin signaling appears to be of crucial biological importance in synovial sarcoma tumorigenesis and progression, representing a potential molecular target for the development of novel therapeutic strategies.

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Acknowledgements

PKF115-584, CGP049090 and PKF118–310 were generously provided by A Wood (Novartis Pharma AG, Basel, Switzerland). This study was supported by Wilhelm Sander-Stiftung, Dr Eberhard und Hilde Rüdiger Stiftung, Deutsche Krebshilfe (KoSar sarcoma competence network), BONFOR (Medical Faculty, University Hospital Bonn, Bonn) and Fortune program (Medical Faculty, University of Cologne, Cologne).

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Authors and Affiliations

  1. Department of Pathology, University Hospital Cologne, Cologne, Germany

    M Trautmann, E Sievers, D Kindler, S Michels, N Friedrichs, S Huss, E Wardelmann, R Büttner & W Hartmann

  2. Department of Pathology, University Hospital Bonn, Bonn, Germany

    M Trautmann, J Kirfel & S Steiner

  3. Institute of Human Genetics, University of Bonn, Bonn, Germany

    S Aretz

  4. Department of Pathology, University Hospital Heidelberg, Heidelberg, Germany

    M Renner, R Penzel, P Schirmacher & G Mechtersheimer

  5. Department of Neuropathology, Charité-Universitätsmedizin, Berlin, Germany

    A Koch

  6. Departments of Oncology & Pathology, The Karolinska Institute, Stockholm, Sweden

    O Larsson

  7. Division of Orthopaedic Surgery, National Cancer Center Hospital, Tokyo, Japan

    A Kawai

  8. Laboratory of Molecular & Cellular Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan

    S Tanaka

  9. Department of Laboratory Medicine, Chungoku Central Hospital, Fukuyama, Hiroshima, Japan

    H Sonobe

  10. Department of Neuropathology, University Hospital Bonn, Bonn, Germany

    A Waha

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Correspondence to W Hartmann.

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Competing interests

E Wardelmann has received honoraria from speakers’ bureau of Novartis Oncology, MSD and Eisai, and is a scientific consultant/advisory board member of Novartis Oncology and MSD. The remaining authors declare no conflict of interest.

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Trautmann, M., Sievers, E., Aretz, S. et al. SS18-SSX fusion protein-induced Wnt/β-catenin signaling is a therapeutic target in synovial sarcoma. Oncogene 33, 5006–5016 (2014). https://doi.org/10.1038/onc.2013.443

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  • DOI: https://doi.org/10.1038/onc.2013.443

Keywords

  • Synovial sarcoma
  • SYT-SSX
  • β-catenin
  • Wnt signaling pathway
  • PKF115-584
  • CGP049090
  • PKF118-310

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