The SS18-SSX Oncoprotein Hijacks KDM2B-PRC1.1 to Drive Synovial Sarcoma

Abstract

Synovial sarcoma is an aggressive cancer invariably associated with a chromosomal translocation involving genes encoding the SWI-SNF complex component SS18 and an SSX (SSX1 or SSX2) transcriptional repressor. Using functional genomics, we identify KDM2B, a histone demethylase and component of a non-canonical polycomb repressive complex 1 (PRC1.1), as selectively required for sustaining synovial sarcoma cell transformation. SS18-SSX1 physically interacts with PRC1.1 and co-associates with SWI/SNF and KDM2B complexes on unmethylated CpG islands. Via KDM2B, SS18-SSX1 binds and aberrantly activates expression of developmentally regulated genes otherwise targets of polycomb-mediated repression, which is restored upon KDM2B depletion, leading to irreversible mesenchymal differentiation. Thus, SS18-SSX1 deregulates developmental programs to drive transformation by hijacking a transcriptional repressive complex to aberrantly activate gene expression.

Tumor-associated macrophages and macrophage-related immune checkpoint expression in sarcomas

“…From the University of British Columbia Genetic Pathology Evaluation Center (Vancouver, BC, Canada), 14 formalinfixed, paraffin-embedded tissue microarrays (TMAs) were included: TMA 01-003 (synovial sarcoma and differential diagnoses, 82 cases in duplicate); 47 TMA 03-008 (chondroid tumors, 121 cases in duplicate); 48 TMA 06-001E (gastrointestinal stromal tumors, 129 cases in duplicate); 49 TMA 06-007 (myxoid liposarcomas, 69 cases in triplicate); 50 TMA 09-006 (epithelioid sarcoma and differential diagnoses, 53 cases in duplicate); 51 TMA 10-004 (28 chordomas, in duplicate); TMA 10-009 (8 alveolar soft part sarcomas, 2 alveolar rhabdomyosarcomas, 2 desmoplastic small round cell tumors, in triplicate); 51 TMA 12-004 (BCL2-positive tumors, 35 cases in triplicate); 52 TMA 12-005 (pediatric spindle cell lesions, 134 cases in duplicate); 52 TMA 12-006 (translocation-associated sarcomas, 10 cases in duplicate); 52 TMA 12-010 (5 dedifferentiated liposarcomas and 5 undifferentiated pleomorphic sarcomas, in duplicate); 52 TMA 14-006 (4 myxoid liposarcomas, 3 myxofibrosarcomas, 3 chondrosarcomas, 1 synovial sarcoma, 1 malignant peripheral nerve sheath tumor, in duplicate); 53 TMA 14-007 (dedifferentiated liposarcomas with well-differentiated areas, both components for 57 cases in duplicate); 54 and TMA MPNST (malignant peripheral nerve sheath tumor and differential diagnoses, 176 cases in duplicate). 55 From Mount Sinai Hospital (New York, NY, USA), four TMAs were included: MSH-OSa (osteosarcomas, 280 cases in duplicate); MSH-SS (synovial sarcomas, 70 cases in duplicate); MSH-SFT (solitary fibrous tumors, 140 cases in duplicate); 56 and MSH-UPS (74 undifferentiated pleomorphic sarcomas, 52 myxofibrosarcomas, 18 leiomyosarcomas, 13 dedifferentiated liposarcomas, 9 dermatofibrosarcoma protuberans, and differential diagnoses; 210 cases total in duplicate).…”

“…All antibodies were applied using the Ventana DISCOVERY® ULTRA semi-automated staining system (Ventana Medical Systems Inc., Tucson, AZ), as described previously. 54 Briefly, heat-induced antigen retrieval was performed using the standard Cell Conditioning 1 (CC1, Ventana) protocol. Slides were incubated with primary antibodies (described in Table S1) in DISCOVERY antibody diluent (Ventana) for 2 h at room temperature.…”

Stem cell transcription factor SOX2 in synovial sarcoma and other soft tissue tumors

“…The strength of the SS18-SSX alteration lies in the fact that the fusion gene has influence on two major players in epigenetic regulation. This leads to the inactivation of tumor suppressive functions of the SWI/SNF nucleosome remodeling complex and changes Histone chromatin marks that leads to the activation of the cancer stem cell transcription factor SOX2 as well as other genes that are normally suppressed by the polycomb repressive complexes 1 and 2 (Banito et al 2018).…”

Cooperation between SS18-SSX1 and miR-214 in Synovial Sarcoma Development and Progression

“…In addition, SWI/SNF disruption by SS18-SSX fusion proteins induces activation of WNT/β-catenin signaling [9]. Another study showed that KDM2B and polycomb repressive complex 1 recruits SS18-SSX1 proteins and the SWI/SNF complex to unmethylated CpG islands, leading to aberrant activation of gene expression [10]. Although PTEN, CTNNB1, and APC mutations have been reported in synovial sarcoma, the frequency of secondary mutations in this disease is not very high [11].…”