SMARCE1 deficiency generates a targetable mSWI/SNF dependency in clear cell meningioma

Pierre, Roodolph St.; Collings, Clayton K.; Guerra, Daniel Samé; Widmer, Christian J.; Bolonduro, Olubusayo; Mashtalir, Nazar; Sankar, Akshay; Liang, Yu; Bi, Wenya Linda; Gerkes, Erica H.; Ramesh, Vijaya; Qi, Jun; Smith, Miriam J.; Meredith, David M.; Kadoch, Cigall

doi:10.1038/s41588-022-01077-0

Cited by 26 publications

(17 citation statements)

References 75 publications

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“…While histopathology continued to drive the contemporary grading of meningiomas, interesting corollaries between pathological subtype and molecular findings have been uncovered SMARCE1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1) mutations were found in almost all cases of meningiomas with clear cell histology (WHO grade 2) and are often mutually exclusively with NF2 loss and non- NF2 mutations [ 26 – 29 ]. Subsequent studies demonstrated SMARCE1 loss to be associated with reduced DNA accessibility over distal enhancer sites, and SMARCE1 -deficient cells were susceptible to mSWI/SNF inhibition [ 29 ]. Another rare alteration in aggressive meningiomas was inactivation of BAP1 [breast cancer (BRCA)1-associated protein-1 tumor suppressor] [ 30 – 32 ].…”

Section: Introductionmentioning

confidence: 99%

The multiomic landscape of meningiomas: a review and update

et al. 2023

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Purpose Meningiomas are the most common primary brain tumor in adults. Traditionally they have been understudied compared to other central nervous system (CNS) tumors. However over the last decade, there has been renewed interest in uncovering the molecular topography of these tumors, with landmark studies identifying key driver alterations contributing to meningioma development and progression. Recent work from several independent research groups have integrated different genomic and epigenomic platforms to develop a molecular-based classification scheme for meningiomas that could supersede histopathological grading in terms of diagnostic accuracy, biological relevance, and outcome prediction, keeping pace with contemporary grading schemes for other CNS tumors including gliomas and medulloblastomas. Methods Here we summarize the studies that have uncovered key alterations in meningiomas which builds towards the discovery of consensus molecular groups in meningiomas by integrating these findings. These groups supersede WHO grade and other clinical factors in being able to accurately predict tumor biology and clinical outcomes following surgery. Results Despite differences in the nomenclature of recently uncovered molecular groups across different studies, the biological similarities between these groups enables us to likely reconciliate these groups into four consensus molecular groups: two benign groups largely dichotomized by NF2-status, and two clinically aggressive groups defined by their hypermetabolic transcriptome, and by their preponderance of proliferative, cell-cycling pathways respectively. Conclusion Future work, including by our group and others are underway to validate these molecular groups and harmonize the nomenclature for routine clinical use.

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Section: Introductionmentioning

confidence: 99%

The multiomic landscape of meningiomas: a review and update

et al. 2023

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“…SMARCE1 incorporates into cBAF and PBAF, but not ncBAF (Mashtalir et al ., 2018). Importantly, it has been recently demonstrated that in clear cell meningioma (CCM), driven by loss of SMARCE1, the cBAF complex fails to stabilize on chromatin, attenuating its activity (St Pierre et al, 2022).…”

Section: Resultsmentioning

confidence: 99%

“…The role of SMARCE1 in sustaining the integrity of the cBAF complex, by bolstering the connectivity between the unique cBAF component, ARID1A, and core module constituents, like SMARCB1, has already been described (St Pierre et al, 2022). Supporting the hypothesis of cBAF complex stabilization following TAK-981 treatment and subsequent SMARCE1 upregulation, we observed an increase in fellow cBAF members ARID1A, and SMARCB1 (BAF47) in SYO-1 and HS-SY-II cells in the presence of TAK-981 (Fig.…”

Section: Sumoylation Inhibition Stabilizes the Cbaf Complexmentioning

confidence: 94%

Targeting of SUMOylation leads to cBAF complex stabilization and disruption of the SS18::SSX transcriptome in Synovial Sarcoma

Floros,

Fairchild,

et al. 2024

Preprint

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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 subunit SMARCE1, stabilizing and restoring cBAF on chromatin, shifting away from SS18::SSX-ncBAF-driven transcription, associated with DNA damage and cell death and resulting in 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-ncBAF transcriptome, identifying a therapeutic vulnerability in SS, positioning the in-clinic TAK-981 to treat SS

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“…It was found that human SWI/SNF chromatinremodeling complex consists of 9~12 subunits, and SMARCE1 was one of the subunits of human SWI/SNF chromatin remodeling complex [16]. The human SWI/SNF chromatin-remodeling complex contains one of the AT-Pases of the SMARCA4 or SMARCA4 and three major core subunits and other complex specific variant subunits.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic Value of SMARCE1 and CRISP3 Combined with Tumor Markers in Cervical Cancer

He¹,

Wang²,

Zhang³

2023

Clin. Exp. Obstet. Gynecol.

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Background: To investigate the diagnostic value of SMARCE1, cysteine-rich secreted protein 3 (CRISP3) combined with tumor markers in the diagnosis of cervical cancer. Methods: A total of 80 patients with cervical lesions who were diagnosed and treated in our hospital from January 2020 to March 2022 were selected and divided into control group (chronic cervicitis, n = 30) and observation group (cervical cancer, n = 50). Immunohistochemistry was used to detect the expression levels of SMARCE1 and CRISP3 in cervical tissue of the two groups of subjects, and the relationship between the expression of SMARCE1 and CRISP3 in cervical cancer tissue and the clinicopathological data of the patients was analyzed. In addition, the serum tumor marker levels of the two groups of subjects were detected, and the diagnostic value of SMARCE1 and CRISP3 combined with tumor markers in cervical cancer was analyzed. The female sexual function index (FSFI) and the functional assessment of cancer therapy-general (FACT-G) score were used to evaluate female sexual function and quality of life. Results: The positive expression rates of SMARCE1 and CRISP3 in the observation group were significantly higher than those in the control group (p < 0.05). There was no significant difference in the positive expression of SMARCE1 and CRISP3 among cervical cancer patients with age, lymph node metastasis and tumor node metastasis (TNM) classification stage (p > 0.05), and the lower the degree of tumor differentiation, the higher the positive expression rate of SMARCE1 and CRISP3 proteins (p < 0.05). The serum levels of carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 125 and CA153 in the observation group were significantly higher than those in the control group (p < 0.05). The results of the receiver operating characteristic (ROC) curve analysis showed that the area under curve (AUC) values of SMARCE1, SMARCE1 + tumor markers, CRISP3, CRISP3 + tumor markers, SMARCE1, CRISP3 combined with tumor markers for the diagnosis of cervical cancer were 0.760, 0.851, 0.739, 0.810, and 0.944, respectively. Conclusions: SMARCE1 and CRISP3 are expressed in patients with cervical cancer, and CEA, CA125, and CA153 are expressed at high levels in the serum of patients with cervical cancer. The combined detection of SMARCE1 and CRISP3 combined with tumor markers has high clinical diagnostic value for cervical cancer.

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SMARCE1 deficiency generates a targetable mSWI/SNF dependency in clear cell meningioma

Cited by 26 publications

References 75 publications

The multiomic landscape of meningiomas: a review and update

The multiomic landscape of meningiomas: a review and update

Targeting of SUMOylation leads to cBAF complex stabilization and disruption of the SS18::SSX transcriptome in Synovial Sarcoma

Diagnostic Value of SMARCE1 and CRISP3 Combined with Tumor Markers in Cervical Cancer

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