SS18::SSX redistributes BAF chromatin remodelers selectively to activate and repress transcription [ChIP-Seq, Hi-ChIP]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE269770 | GEO | 2025/06/10
REPOSITORIES: GEO
Similar Datasets
Project description:Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin remodeling BAF (mammalian SWI/SNF) complexes, leading to the degradation of canonical (cBAF) complex and amplified presence of an SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) that drives an SS-specific transcription program and tumorigenesis. We demonstrate that SS18::SSX activates the SUMOylation program and SSs are sensitive to the small molecule SAE1/2 inhibitor, TAK-981. Mechanistically, TAK-981 de-SUMOylates the cBAF/PBAF component, SMARCE1, stabilizing and restoring cBAF on chromatin, shifting away from SS18::SSX-driven transcription, resulting in DNA damage, cell death and tumor inhibition across both human and mouse SS tumor models. TAK-981 synergized with cytotoxic chemotherapy through increased DNA damage, leading to tumor regression. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX transcriptome, identifying a therapeutic vulnerability in SS.
2025-08-07 | PXD059936 | Pride
Project description:Synovial sarcoma (SS) is a rare malignancy, involves a t(X;18) chromosomal translocation that creates a fusion gene SS18-SSX. SS18 is a chromatin remodeling BAF-complexes component, which incorporated in CBAF and GBAF (non-canonical ncBAF). Our previous studies determined that incorporation of the fusion oncoprotein caused degradation of CBAF complexes, emphasizing a critical oncogenic function of GBAF and PBAF in synovial sarcomagenesis. To determine the SyS dependencies on different subtypes of BAF complexes during tumor development in vivo, we used our SyS mouse model combined with genetic disruption of specific BAF complexes components ARID1A/B or PBRM1. In this study, our fundings suggest that depletion of ARID1A and ARID1B sped tumorigenesis, without significant change in the histomorphology of the developing tumors. Loss of PBRM1 also led to faster tumor growing, but Pbrm1-silenced tumors lacked the full array of SyS histomorphologies observed in wildtype tumors. Overall, Arid1a or Arid1b disruption rendered tumor transcriptomes that clustered within the hSS2 tumor transcriptomes, unlike Pbrm1 disrupted tumors.
2025-06-10 | GSE269772 | GEO
Project description:Synovial Sarcoma (SS) is driven by the SS18::SSX translocation event and is often diagnosed in patients under 30. In general, SS is refractory to chemotherapy and other therapeutic approaches. SS18::SSX does not directly bind to DNA. Instead, SS18::SSX alters ATP-dependent chromatin remodeling complex BAF (mammalian SWI/SNF complex) complexes away from a wild-type SS18-containing canonical (cBAF) complex towards a SS18::SSX-containing non-canonical (nc)BAF complex to drive a SS-specific transcription program with subsequent tumor formation. Small molecule targeted therapies are expanding beyond the kinome, providing additional tools to treat cancers that are not yet amenable to targeted therapies. Here, we demonstrate that SS18::SSX activates the SUMOylation program and SS are sensitive to the small molecule SAE1/2 inhibitor, TAK-981 (subasumstat). Mechanistically, we demonstrate TAK-981 de-SUMOylates the cBAF and Polybromo-associated BAF complex (PBAF) complex member, SMARCE1. The result of which is stabilization and restoration of cBAF complexes on chromatin, shifting away from the dominant SS18::SSX-ncBAF-complex driven transcriptome. This phenotypic shift is associated with DNA damage and cell death, resulting in tumor inhibition across both human and mouse SS tumor models. As such, TAK-981 combined with standard-of-care chemotherapy enhances induced synergistic activity through increased DNA damage, leading to tumor regressions. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX-ncBAF transcriptome, identifying a therapeutic vulnerability in SS, and positioning the in-clinic TAK-981 as a novel candidate to treat this refractory cancer.
2025-08-06 | GSE266134 | GEO
Project description:Synovial Sarcoma (SS) is driven by the SS18::SSX translocation event and is often diagnosed in patients under 30. In general, SS is refractory to chemotherapy and other therapeutic approaches. SS18::SSX does not directly bind to DNA. Instead, SS18::SSX alters ATP-dependent chromatin remodeling complex BAF (mammalian SWI/SNF complex) complexes away from a wild-type SS18-containing canonical (cBAF) complex towards a SS18::SSX-containing non-canonical (nc)BAF complex to drive a SS-specific transcription program with subsequent tumor formation. Small molecule targeted therapies are expanding beyond the kinome, providing additional tools to treat cancers that are not yet amenable to targeted therapies. Here, we demonstrate that SS18::SSX activates the SUMOylation program and SS are sensitive to the small molecule SAE1/2 inhibitor, TAK-981 (subasumstat). Mechanistically, we demonstrate TAK-981 de-SUMOylates the cBAF and Polybromo-associated BAF complex (PBAF) complex member, SMARCE1. The result of which is stabilization and restoration of cBAF complexes on chromatin, shifting away from the dominant SS18::SSX-ncBAF-complex driven transcriptome. This phenotypic shift is associated with DNA damage and cell death, resulting in tumor inhibition across both human and mouse SS tumor models. As such, TAK-981 combined with standard-of-care chemotherapy enhances induced synergistic activity through increased DNA damage, leading to tumor regressions. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX-ncBAF transcriptome, identifying a therapeutic vulnerability in SS, and positioning the in-clinic TAK-981 as a novel candidate to treat this refractory cancer.
2025-08-06 | GSE266206 | GEO
Project description:Synovial Sarcoma (SS) is driven by the SS18::SSX translocation event and is often diagnosed in patients under 30. In general, SS is refractory to chemotherapy and other therapeutic approaches. SS18::SSX does not directly bind to DNA. Instead, SS18::SSX alters ATP-dependent chromatin remodeling complex BAF (mammalian SWI/SNF complex) complexes away from a wild-type SS18-containing canonical (cBAF) complex towards a SS18::SSX-containing non-canonical (nc)BAF complex to drive a SS-specific transcription program with subsequent tumor formation. Small molecule targeted therapies are expanding beyond the kinome, providing additional tools to treat cancers that are not yet amenable to targeted therapies. Here, we demonstrate that SS18::SSX activates the SUMOylation program and SS are sensitive to the small molecule SAE1/2 inhibitor, TAK-981 (subasumstat). Mechanistically, we demonstrate TAK-981 de-SUMOylates the cBAF and Polybromo-associated BAF complex (PBAF) complex member, SMARCE1. The result of which is stabilization and restoration of cBAF complexes on chromatin, shifting away from the dominant SS18::SSX-ncBAF-complex driven transcriptome. This phenotypic shift is associated with DNA damage and cell death, resulting in tumor inhibition across both human and mouse SS tumor models. As such, TAK-981 combined with standard-of-care chemotherapy enhances induced synergistic activity through increased DNA damage, leading to tumor regressions. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX-ncBAF transcriptome, identifying a therapeutic vulnerability in SS, and positioning the in-clinic TAK-981 as a novel candidate to treat this refractory cancer.
2025-08-06 | GSE266203 | GEO
Project description:Synovial Sarcoma (SS) is driven by the SS18::SSX translocation event and is often diagnosed in patients under 30. In general, SS is refractory to chemotherapy and other therapeutic approaches. SS18::SSX does not directly bind to DNA. Instead, SS18::SSX alters ATP-dependent chromatin remodeling complex BAF (mammalian SWI/SNF complex) complexes away from a wild-type SS18-containing canonical (cBAF) complex towards a SS18::SSX-containing non-canonical (nc)BAF complex to drive a SS-specific transcription program with subsequent tumor formation. Small molecule targeted therapies are expanding beyond the kinome, providing additional tools to treat cancers that are not yet amenable to targeted therapies. Here, we demonstrate that SS18::SSX activates the SUMOylation program and SS are sensitive to the small molecule SAE1/2 inhibitor, TAK-981 (subasumstat). Mechanistically, we demonstrate TAK-981 de-SUMOylates the cBAF and Polybromo-associated BAF complex (PBAF) complex member, SMARCE1. The result of which is stabilization and restoration of cBAF complexes on chromatin, shifting away from the dominant SS18::SSX-ncBAF-complex driven transcriptome. This phenotypic shift is associated with DNA damage and cell death, resulting in tumor inhibition across both human and mouse SS tumor models. As such, TAK-981 combined with standard-of-care chemotherapy enhances induced synergistic activity through increased DNA damage, leading to tumor regressions. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX-ncBAF transcriptome, identifying a therapeutic vulnerability in SS, and positioning the in-clinic TAK-981 as a novel candidate to treat this refractory cancer.
2025-08-06 | GSE266201 | GEO
Project description:Synovial Sarcoma (SS) is driven by the SS18::SSX translocation event and is often diagnosed in patients under 30. In general, SS is refractory to chemotherapy and other therapeutic approaches. SS18::SSX does not directly bind to DNA. Instead, SS18::SSX alters ATP-dependent chromatin remodeling complex BAF (mammalian SWI/SNF complex) complexes away from a wild-type SS18-containing canonical (cBAF) complex towards a SS18::SSX-containing non-canonical (nc)BAF complex to drive a SS-specific transcription program with subsequent tumor formation. Small molecule targeted therapies are expanding beyond the kinome, providing additional tools to treat cancers that are not yet amenable to targeted therapies. Here, we demonstrate that SS18::SSX activates the SUMOylation program and SS are sensitive to the small molecule SAE1/2 inhibitor, TAK-981 (subasumstat). Mechanistically, we demonstrate TAK-981 de-SUMOylates the cBAF and Polybromo-associated BAF complex (PBAF) complex member, SMARCE1. The result of which is stabilization and restoration of cBAF complexes on chromatin, shifting away from the dominant SS18::SSX-ncBAF-complex driven transcriptome. This phenotypic shift is associated with DNA damage and cell death, resulting in tumor inhibition across both human and mouse SS tumor models. As such, TAK-981 combined with standard-of-care chemotherapy enhances induced synergistic activity through increased DNA damage, leading to tumor regressions. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX-ncBAF transcriptome, identifying a therapeutic vulnerability in SS, and positioning the in-clinic TAK-981 as a novel candidate to treat this refractory cancer.
2025-08-06 | GSE266199 | GEO
Project description:Synovial Sarcoma (SS) is driven by the SS18::SSX translocation event and is often diagnosed in patients under 30. In general, SS is refractory to chemotherapy and other therapeutic approaches. SS18::SSX does not directly bind to DNA. Instead, SS18::SSX alters ATP-dependent chromatin remodeling complex BAF (mammalian SWI/SNF complex) complexes away from a wild-type SS18-containing canonical (cBAF) complex towards a SS18::SSX-containing non-canonical (nc)BAF complex to drive a SS-specific transcription program with subsequent tumor formation. Small molecule targeted therapies are expanding beyond the kinome, providing additional tools to treat cancers that are not yet amenable to targeted therapies. Here, we demonstrate that SS18::SSX activates the SUMOylation program and SS are sensitive to the small molecule SAE1/2 inhibitor, TAK-981 (subasumstat). Mechanistically, we demonstrate TAK-981 de-SUMOylates the cBAF and Polybromo-associated BAF complex (PBAF) complex member, SMARCE1. The result of which is stabilization and restoration of cBAF complexes on chromatin, shifting away from the dominant SS18::SSX-ncBAF-complex driven transcriptome. This phenotypic shift is associated with DNA damage and cell death, resulting in tumor inhibition across both human and mouse SS tumor models. As such, TAK-981 combined with standard-of-care chemotherapy enhances induced synergistic activity through increased DNA damage, leading to tumor regressions. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX-ncBAF transcriptome, identifying a therapeutic vulnerability in SS, and positioning the in-clinic TAK-981 as a novel candidate to treat this refractory cancer.
2025-08-06 | GSE266276 | GEO
Project description:Synovial Sarcoma (SS) is driven by the SS18::SSX translocation event and is often diagnosed in patients under 30. In general, SS is refractory to chemotherapy and other therapeutic approaches. SS18::SSX does not directly bind to DNA. Instead, SS18::SSX alters ATP-dependent chromatin remodeling complex BAF (mammalian SWI/SNF complex) complexes away from a wild-type SS18-containing canonical (cBAF) complex towards a SS18::SSX-containing non-canonical (nc)BAF complex to drive a SS-specific transcription program with subsequent tumor formation. Small molecule targeted therapies are expanding beyond the kinome, providing additional tools to treat cancers that are not yet amenable to targeted therapies. Here, we demonstrate that SS18::SSX activates the SUMOylation program and SS are sensitive to the small molecule SAE1/2 inhibitor, TAK-981 (subasumstat). Mechanistically, we demonstrate TAK-981 de-SUMOylates the cBAF and Polybromo-associated BAF complex (PBAF) complex member, SMARCE1. The result of which is stabilization and restoration of cBAF complexes on chromatin, shifting away from the dominant SS18::SSX-ncBAF-complex driven transcriptome. This phenotypic shift is associated with DNA damage and cell death, resulting in tumor inhibition across both human and mouse SS tumor models. As such, TAK-981 combined with standard-of-care chemotherapy enhances induced synergistic activity through increased DNA damage, leading to tumor regressions. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX-ncBAF transcriptome, identifying a therapeutic vulnerability in SS, and positioning the in-clinic TAK-981 as a novel candidate to treat this refractory cancer.
2025-08-06 | GSE266207 | GEO
Project description:Synovial Sarcoma (SS) is driven by the SS18::SSX translocation event and is often diagnosed in patients under 30. In general, SS is refractory to chemotherapy and other therapeutic approaches. SS18::SSX does not directly bind to DNA. Instead, SS18::SSX alters ATP-dependent chromatin remodeling complex BAF (mammalian SWI/SNF complex) complexes away from a wild-type SS18-containing canonical (cBAF) complex towards a SS18::SSX-containing non-canonical (nc)BAF complex to drive a SS-specific transcription program with subsequent tumor formation. Small molecule targeted therapies are expanding beyond the kinome, providing additional tools to treat cancers that are not yet amenable to targeted therapies. Here, we demonstrate that SS18::SSX activates the SUMOylation program and SS are sensitive to the small molecule SAE1/2 inhibitor, TAK-981 (subasumstat). Mechanistically, we demonstrate TAK-981 de-SUMOylates the cBAF and Polybromo-associated BAF complex (PBAF) complex member, SMARCE1. The result of which is stabilization and restoration of cBAF complexes on chromatin, shifting away from the dominant SS18::SSX-ncBAF-complex driven transcriptome. This phenotypic shift is associated with DNA damage and cell death, resulting in tumor inhibition across both human and mouse SS tumor models. As such, TAK-981 combined with standard-of-care chemotherapy enhances induced synergistic activity through increased DNA damage, leading to tumor regressions. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX-ncBAF transcriptome, identifying a therapeutic vulnerability in SS, and positioning the in-clinic TAK-981 as a novel candidate to treat this refractory cancer.
2025-08-06 | GSE266066 | GEO