Abstract
Synovial sarcoma is a soft tissue malignancy characterized by a reciprocal t(X;18) translocation. The chimeric SS18-SSX fusion protein acts as a transcriptional dysregulator representing the major driver of the disease; however, the signaling pathways activated by SS18-SSX remain to be elucidated to define innovative therapeutic strategies. Immunohistochemical evaluation of the Hippo signaling pathway effectors YAP/TAZ was performed in a large cohort of synovial sarcoma tissue specimens. SS18-SSX dependency and biological function of the YAP/TAZ Hippo signaling cascade were analyzed in five synovial sarcoma cell lines and a mesenchymal stem cell model in vitro. YAP/TAZ-TEAD-mediated transcriptional activity was modulated by RNAi-mediated knockdown and the small-molecule inhibitor verteporfin. The effects of verteporfin were finally tested in vivo in synovial sarcoma cell line-based avian chorioallantoic membrane and murine xenograft models as well as a patient-derived xenograft. A significant subset of synovial sarcoma showed nuclear positivity for YAP/TAZ and their transcriptional targets FOXM1 and PLK1. In synovial sarcoma cells, RNAi-mediated knockdown of SS18-SSX led to significant reduction of YAP/TAZ-TEAD transcriptional activity. Conversely, SS18-SSX overexpression in SCP-1 cells induced aberrant YAP/TAZ-dependent signals, mechanistically mediated by an IGF-II/IGF-IR signaling loop leading to dysregulation of the Hippo effectors LATS1 and MOB1. Modulation of YAP/TAZ-TEAD-mediated transcriptional activity by RNAi or verteporfin treatment resulted in significant growth inhibitory effects in vitro and in vivo. Our preclinical study identifies an elementary role of SS18-SSX-driven YAP/TAZ signals, highlights the complex network of oncogenic signaling pathways in synovial sarcoma pathogenesis, and provides evidence for innovative therapeutic approaches.
Highlights
Synovial sarcoma (SySa) is an aggressive malignancy comprising approximately 2% of all sarcomas with a predominance in adolescents and young adults [1, 2]
RNA interference (RNAi)-mediated knockdown of SS18-SSX led to significant reduction of YAP/TAZ-TEAD transcriptional activity
Modulation of YAP/TAZ-TEAD–mediated transcriptional activity by RNAi or verteporfin treatment resulted in significant growth inhibitory effects in vitro and in vivo
Summary
Synovial sarcoma (SySa) is an aggressive malignancy comprising approximately 2% of all sarcomas with a predominance in adolescents and young adults [1, 2]. Specific molecularly targeted therapeutic approaches are currently limited. The molecular hallmark of SySa is a pathognomonic reciprocal t(X;18)(p11;q11) translocation, leading to the fusion of SS18 (SYT) and one of the homologues SSX genes (most frequently SSX1 or SSX2, in rare cases SSX4), generating chimeric SS18-SSX fusion proteins [6,7,8]. The SS18SSX protein is known to play a crucial role in SySa tumorigenesis, its specific biological function and its mechanism of action remain to be elucidated. Neither SS18 and the SSX proteins, nor the chimeric SS18-SSX oncoproteins feature known DNA-binding motifs; they have been reported to contribute to the dysregulation of gene expression through association with SWI/SNF and Polycomb chromatin remodeling complexes [8,9,10,11,12]
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