A Role for SMARCB1 in Synovial Sarcomagenesis Reveals That SS18–SSX Induces Canonical BAF Destruction

Abstract

Reduced protein levels of SMARCB1 (a.k.a. BAF47, INI1, SNF5) have long been observed in synovial sarcoma (SS). Here, we show that combined Smarcb1 genetic loss with SS18-SSX expression in mice synergized to produce aggressive tumors with histomorphology, transcriptomes, and genome-wide BAF-family complex distributions distinct from SS18-SSX alone, indicating a defining role for SMARCB1 in SS. Smarcb1 silencing alone in mesenchyme modeled epithelioid sarcomagenesis. In mouse and human SS cells, SMARCB1 was identified within PBAF and canonical BAF (CBAF) complexes, co-incorporated with SS18-SSX in the latter. Recombinant expression of CBAF components in human cells reconstituted CBAF sub-complexes that contained equal levels of SMARCB1, regardless of SS18 or SS18-SSX inclusion. In vivo, SS18-SSX expression led to whole-complex CBAF degradation, rendering increases in the relative prevalence of other BAF-family subtypes, PBAF and GBAF complexes, over time. Thus, SS18-SSX alters BAF subtypes levels/balance and genome distribution, driving synovial sarcomagenesis.Research.

SMARCB1 expression is a novel diagnostic and prognostic biomarker for osteosarcoma

“…We confirmed similar results at the gene expression level by in-silico analysis using mRNA-seq and clinicopathological data from the TARGET-OS project. Our findings are consistent with previous works that support the anti-tumorigenic role of SMARCB1 [ 14 , 27 , 30 ]. To our knowledge, this study is the first to show SMARCB1 expression as a potential prognostic biomarker and indicator of advanced disease status in osteosarcoma.…”

Phase transition and remodeling complex assembly are important for SS18-SSX oncogenic activity in synovial sarcomas

“…On the other hand, other studies suggest that SS18-SSX alters BAF genome distribution and subtype levels and therefore increases the complex’s ability to disrupt PRC2 function. This disruption could mediate activation of gene expression through the COMPASS family of histone H3K4 methylases and orchestrate aberrant oncogenic transcriptional programs 13 , 38 , 39 . A study from Banito et al found that SS18-SSX fusions associate with KDM2B-PRC1.1, a noncanonical polycomb repressive complex 1, to aberrantly activate transcription factors that are targets of polycomb-mediated gene repression 40 .…”

Integrative multi-omics analysis reveals molecular subtypes and tumor evolution of synovial sarcoma

“…SS18-SSX may induce degradation of the canonical BAF-complex (cBAF). Since we observed significantly higher expression of the polybromo-associated BAF (pBAF) specific components ARID2 , SMARCE1 and PHF10 in SSC-I, it is implied that SSC-I is dominated by the pBAF complex [50, 51]. SCNAs were similar to vascularized SS (SSC-II) and evidently less frequent than in epithelial-SS (SSC-III), indicating that the hyperproliferative phenotype arises de novo and is not a progression from SSC-II/III.…”