Abstract 388: SS18-SSX modulates YAP/TAZ-TEAD transcriptional activity in synovial sarcoma
Authors: Isfort Ilka , Cyra Magdalene , Elges Sandra , Kailayangiri Sareetha , Altvater Bianca , Rossig Claudia , Mikesch Jan-Henrik , Wozniak Agnieszka , Schöffski Patrick , Wardelmann Eva , Trautmann Marcel , Hartmann Wolfgang 
Published: August 2019

Abstract
Introduction: Synovial sarcoma (SySa) is a rare soft-tissue malignancy characterized by a specific reciprocal translocation t(X;18). The resulting chimeric SS18-SSX fusion protein acts as transcriptional dysregulator representing the major oncogenic driver in SySa tumorigenesis. Since targeting the fusion protein itself remains a particular challenge, it appears reasonable to therapeutically address signaling pathways which are functionally dependent on the SS18-SSX fusion protein. As different tumor entities were recently shown to harbor aberrant Hippo signaling patterns leading to increased activity of the transcriptional coactivators YAP/TAZ, the aim of this study was to analyze the role of YAP/TAZ in SySa and to decipher the functional link to the SS18-SSX fusion protein.
Experimental procedures: YAP/TAZ expression was analyzed by immunohistochemistry in a large cohort of SySa tissue specimens (n=65). Five SySa cell lines and mesenchymal SCP-1 stem cells stably expressing the SS18-SSX fusion protein were employed for in vitro analyses. We set out to analyze whether YAP/TAZ-TEAD transcriptional activity is dependent on the SySa-specific fusion protein, if this dependency is mediated by IGF-IR signaling (known to be activated in SySa) and to understand the biological function of YAP/TAZ in SySa. To modulate YAP/TAZ-TEAD transcriptional activity, RNAi-mediated knockdown and the small molecule inhibitor verteporfin were applied. Finally, the therapeutic effect of YAP/TAZ inhibition was tested in vivo using SySa cell line-based and patient-derived xenografts.
Results: SySa tissue specimens and cell lines strongly expressed nuclear YAP/TAZ. RNAi-mediated knockdown of SS18-SSX fusion protein led to significant reduction of YAP/TAZ-TEAD transcriptional activity while SS18-SSX overexpression in SCP-1 cells induced aberrant YAP/TAZ signals. This regulatory connection was at least partly realized through an IGF-II/IGF-IR loop, in which the SS18-SSX fusion protein drives IGF2 expression causing dysregulation of the Hippo effectors LATS1 and MOB1, eventually leading to YAP/TAZ activation. Inhibition of YAP/TAZ-TEAD transcriptional activity by RNAi or verteporfin resulted in a significant induction of apoptosis and significant reduction of SySa cell growth in vitro and in vivo.
Conclusions: Our study reveals SS18-SSX fusion protein-driven YAP/TAZ-TEAD signals to play an elementary role in SySa. Given the high efficacy of YAP/TAZ-directed pharmacological approaches in SySa xenografts, this preclinical study may constitute the basis for a novel therapeutic strategy to inhibit SS18-SSX-driven tumorigenesis.
Citation Format: Ilka Isfort, Magdalene Cyra, Sandra Elges, Sareetha Kailayangiri, Bianca Altvater, Claudia Rossig, Jan-Henrik Mikesch, Agnieszka Wozniak, Patrick Schöffski, Eva Wardelmann, Marcel Trautmann, Wolfgang Hartmann. SS18-SSX modulates YAP/TAZ-TEAD transcriptional activity in synovial sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 388.