Synovial Sarcoma: A Complex Disease with Multifaceted Signaling and Epigenetic Landscapes

Beaino, Marc El; Rassy, Elie El; Hadid, Bana; Araujo, Dejka M.; Pavlidis, Nicholas; Lin, Patrick P.

doi:10.1007/s11912-020-00985-w

Cited by 9 publications

(8 citation statements)

References 165 publications

(303 reference statements)

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“…In contrast to other translocated proteins, the SS18::SSX fusion protein lacks a DNA binding domain and is not a direct transcription factor. It is derived from the substitution of SS18 carboxy-terminal residues with an SSX carboxy-terminal tail [9]. Native SS18 is a member of the multimeric structure switch/sucrose non-fermentable (SWI/SNF) chromatin-remodeling complex family, also known as BRG1/BRM-associated factor (BAF) complexes, which are multimeric structures assembled of at least 29 different proteins.…”

Section: Sys Molecular Biologymentioning

confidence: 99%

“…The de novo, gain-of-function targeting of BAF complexes activates the unique SyS gene expression signature [13], generates multiple epigenetic deregulations, and triggers multiple oncogenic signaling networks [14]. In addition, these fusion genes can directly or indirectly regulate histone deacetylase HDAC1/2 activity [9,15]. Moreover, a repressive role for the SS18::SSX fusion oncoprotein has also been proposed, which is mediated by the PRC2 recruitment to activating transcription factor-2 (ATF2) target genes [9,16].…”

Section: Sys Molecular Biologymentioning

confidence: 99%

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Innovative Breakthroughs for the Treatment of Advanced and Metastatic Synovial Sarcoma

Landuzzi

Manara

Pazzaglia

et al. 2023

Cancers

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Synovial sarcoma (SyS) is a rare aggressive soft tissue sarcoma carrying the chromosomal translocation t(X;18), encoding the fusion transcript SS18::SSX. The fusion oncoprotein interacts with both BAF enhancer complexes and polycomb repressor complexes, resulting in genome-wide epigenetic perturbations and a unique altered genetic signature. Over 80% of the patients are initially diagnosed with localized disease and have a 5-year survival rate of 70–80%, but metastatic relapse occurs in 50% of the cases. Advanced, unresectable, or metastatic disease has a 5-year survival rate below 10%, representing a critical issue. This review summarizes the molecular mechanisms behind SyS and illustrates current treatments in front line, second line, and beyond settings. We analyze the use of immune check point inhibitors (ICI) in SyS that do not behave as an ICI-sensitive tumor, claiming the need for predictive genetic signatures and tumor immune microenvironment biomarkers. We highlight the clinical translation of innovative technologies, such as proteolysis targeting chimera (PROTAC) protein degraders or adoptive transfer of engineered immune cells. Adoptive cell transfer of engineered T-cell receptor cells targeting selected cancer/testis antigens has shown promising results against metastatic SyS in early clinical trials and further improvements are awaited from refinements involving immune cell engineering and tumor immune microenvironment enhancement.

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Section: Sys Molecular Biologymentioning

confidence: 99%

Section: Sys Molecular Biologymentioning

confidence: 99%

Innovative Breakthroughs for the Treatment of Advanced and Metastatic Synovial Sarcoma

Landuzzi

Manara

Pazzaglia

et al. 2023

Cancers

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“…The SM2 (SSM2-Myf5-cre) mice were generated as previously described (7). To create triple mutants SSM2/Myf5-cre/Fgfr (1,2,3) knockout mice, homozygous floxed alleles of FGFRs 1, 2, and 3 (Fgfr1 fl/fl , Fgfr2 fl/fl , and Fgfr3 fl/fl ; 45,46) were mated with SSM2 and Myf5-cre transgenic mice, and then backcrossed to Fgfr floxed mice to obtain double mutants SSM2/Fgfr (1,2,3 fl/f)l and Myf5-cre/Fgfr (1,2,3 fl/fl) .…”

Section: Fgfr1 Fgfr2 and Fgfr3 Are Required For Ss Tumor Formation In Micementioning

confidence: 99%

“…Synovial sarcoma (SS) is a high-grade soft tissue malignancy that disproportionately affects adolescents and young adults. The prognosis of SS patients with advanced disease remains poor with a ~50% 5-year survival rate (1,2). The sarcoma fusions SS18-SSX1 and SS18-SSX2 are distinguished by unique associations with chromatin modifier complexes of opposite functions, SWI/SNF-BAF and polycomb repressive complexes (PRC1 and PRC2).…”

Section: Introductionmentioning

confidence: 99%

ETV4 and ETV5 drive synovial sarcoma through cell cycle and DUX4 embryonic pathway control

DeSalvo¹,

Ban

et al. 2021

Journal of Clinical Investigation

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Synovial sarcoma is an aggressive malignancy with no effective treatments for patients with metastasis. The synovial sarcoma fusion, SS18-SSX, which recruits the SWI/SNF-BAF chromatin remodeling and polycomb repressive complexes, results in epigenetic activation of FGFR signaling. In genetic FGFR knockout models, culture, and xenograft synovial sarcoma models treated with the FGFR inhibitor BGJ398, we show that FGFR1, FGFR2, and FGFR3 were crucial for tumor growth. Transcriptome analyses of BGJ398-treated cells, histological and expression analyses of mouse and human synovial sarcoma tumors revealed prevalent expression of two ETS factors and FGFR targets, ETV4 and ETV5. We further demonstrate that ETV4 and ETV5 acted as drivers of synovial sarcoma growth, most likely through control of the cell cycle. Upon ETV4 and ETV5 knockdown, we observed a striking upregulation of DUX4 and its transcriptional targets that activate the zygotic genome and drive the atrophy program in facioscapulohumeral dystrophy (FSHD) patients. In addition to demonstrating the importance of inhibiting all three FGFR receptors, the current findings reveal potential nodes of attack for the cancer with the discovery of ETV4 and ETV5 as appropriate biomarkers and molecular targets, and activation of the embryonic DUX4 pathway as a promising approach to block synovial sarcoma tumors.

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“…This remarkable translocation is present in virtually 100% of synovial sarcomas and is often the only cytogenetic aberration 1 . Contrasting with conventional translocations in other soft-tissue sarcomas, the oncofusion protein SS18-SSX lacks a DNA binding domain and is thought to exert its activity by combining with other chromatin modifiers 5 .…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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Oncoprotein SS18-SSX is a hallmark of synovial sarcomas. However, as a part of the SS18-SSX fusion protein, SS18’s function remains unclear. Here, we depict the structures of both human SS18/BRG1 and yeast SNF11/SNF2 subcomplexes. Both subcomplexes assemble into heterodimers that share a similar conformation, suggesting that SNF11 might be a homologue of SS18 in chromatin remodeling complexes. Importantly, our study shows that the self-association of the intrinsically disordered region, QPGY domain, leads to liquid-liquid phase separation (LLPS) of SS18 or SS18-SSX and the subsequent recruitment of BRG1 into phase-separated condensates. Moreover, our results show that the tyrosine residues in the QPGY domain play a decisive role in the LLPS of SS18 or SS18-SSX. Perturbations of either SS18-SSX LLPS or SS18-SSX’s binding to BRG1 impair NIH3T3 cell transformation by SS18-SSX. Our data demonstrate that both LLPS and assembling into chromatin remodelers contribute to the oncogenic activity of SS18-SSX in synovial sarcomas.

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Synovial Sarcoma: A Complex Disease with Multifaceted Signaling and Epigenetic Landscapes

Cited by 9 publications

References 165 publications

Innovative Breakthroughs for the Treatment of Advanced and Metastatic Synovial Sarcoma

Innovative Breakthroughs for the Treatment of Advanced and Metastatic Synovial Sarcoma

ETV4 and ETV5 drive synovial sarcoma through cell cycle and DUX4 embryonic pathway control

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

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