SS18::SSX and BRD9 Modulate Synovial Sarcoma Differentiation

Synovial sarcoma (SySa) is a malignant soft tissue tumor that is characterized by an SS18::SSX fusion protein, which integrates into BAF chromatin remodeling complexes and alters global gene transcription. Despite its uniform genetic driver, SySa displays striking histomorphological and phenotypic heterogeneity, including spindle cell, glandular and poorly differentiated patterns. Prognosis is variable, with around 50% of patients developing metastases. Limited response to chemotherapy highlights the need for a better understanding of the underlying molecular mechanisms to guide alternative therapeutic strategies. Given the pivotal function of BAF complexes in SySa and their recently described impact on cellular differentiation processes, this study aims to investigate the role of SS18::SSX and specific BAF subunits in SySa differentiation. Nanostring analysis revealed that silencing of SS18::SSX and the GBAF subunit BRD9 modulates the cellular differentiation pathways. SS18::SSX and BRD9 were found to regulate epithelial–mesenchymal-transition (EMT)-associated factors of Snail and Slug on different levels, with SS18::SSX repressing E-Cadherin expression. Published single-cell RNA sequencing data were analyzed to validate our finding that BRD9 contributes to SySa EMT regulation. Our study provides novel insights into the multilayered regulation of key EMT players by SS18::SSX and BRD9 in SySa, thereby defining tumor phenotype and (potentially) prognosis.