The SS18-SSX Fusion Oncoprotein Hijacks BAF Complex Targeting and Function to Drive Synovial Sarcoma

Abstract

Synovial sarcoma (SS) is defined by the hallmark SS18-SSX fusion oncoprotein, which renders BAF complexes aberrant in two manners: gain of SSX to the SS18 subunit and concomitant loss of BAF47 subunit assembly. Here we demonstrate that SS18-SSX globally hijacks BAF complexes on chromatin to activate an SS transcriptional signature that we define using primary tumors and cell lines. Specifically, SS18-SSX retargets BAF complexes from enhancers to broad polycomb domains to oppose PRC2-mediated repression and activate bivalent genes. Upon suppression of SS18-SSX, reassembly of BAF47 restores enhancer activation, but is not required for proliferative arrest. These results establish a global hijacking mechanism for SS18-SSX on chromatin, and define the distinct contributions of two concurrent BAF complex perturbations.

Immunohistochemical correlates of recurrent genetic alterations in sarcomas

“…However, as around 40% of epithelioid schwannomas also show loss of SMARCB1 expression, this marker cannot be used to distinguish EMPNST from epithelioid schwannoma . Of note, synovial sarcomas usually show markedly reduced (but not complete loss of) SMARCB1 expression, as a result of SWI/SNF complex disruption (and displacement of SMARCB1) by the SS18‐SSX fusion protein …”

Opposing immune and genetic forces shape oncogenic programs in synovial sarcoma

“…SSX genes are a family of CTAs involved in transcriptional repression (14)(15)(16)(17). The resulting SS18-SSX oncoprotein leads to massive dysregulation of the chromatin architecture and transcriptional regulation (11,(18)(19)(20), generating a spectrum of malignant cellular morphologies (4), including counterparts (immune and stroma) grouped primarily by cell type (Fig. 1B,C), as we have observed in other tumor types (28)(29)(30).…”

“…Our study demonstrates that immune evasion, cellular plasticity, and cell cycle are co-regulated and can be co-targeted in synovial sarcoma and potentially in other malignancies. epithelial-like malignant cells (in biphasic tumors), suggestive of pluripotential differentiation or mesenchymal to epithelial transitions.Studies of human SyS to date have either relied on bulk tissue (21,22) or on established cellular models (11,18,19), masking important aspects of the tumor ecosystem. Moreover, given this cancer's rarity, even concerted efforts, such as TCGA, profiled only limited numbers of tumors (21-23).…”

“…Studies of human SyS to date have either relied on bulk tissue (21,22) or on established cellular models (11,18,19), masking important aspects of the tumor ecosystem. Moreover, given this cancer's rarity, even concerted efforts, such as TCGA, profiled only limited numbers of tumors (21-23).…”

Synthetic lethal therapy based on targeting the vulnerability of SWI/SNF chromatin remodeling complex‐deficient cancers

“…SS18 is genetically aberrant because of fusion with SSXs (SSX1, SSX2, or SSX4) in synovial sarcoma. The SS18‐SSX fusion protein is incorporated into the BAF complex, resulting in loss of the SMARCB1 protein from the BAF complex . This suggests that the BAF complex containing the SS18‐SSX fusion protein is deficient in SMARCB1 function.…”