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Shifted assembly and function of mSWI/SNF family subcomplexes underlie targetable dependencies in dedifferentiated endometrial carcinomas

Nature Genetics volume 57, pages 2743–2755 (2025)Cite this article

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Abstract

The mammalian (m)SWI/SNF family of chromatin remodelers govern cell type-specific chromatin accessibility and gene expression and assemble as three distinct complexes: canonical BRG1-associated or BRM-associated factor (cBAF), poly(bromo)-associated BAF (PBAF) and noncanonical BAF (ncBAF). ARID1A and ARID1B are paralog subunits that specifically nucleate the assembly of cBAF complexes and are frequently co-mutated in highly aggressive dedifferentiated or undifferentiated endometrial carcinomas (DDEC/UECs). Here in cellular models and primary human tumors, we find that ARID1A and/or ARID1B (ARID1A/B) deficiency-mediated cBAF loss results in increased ncBAF and PBAF biochemical abundance and chromatin-level functions to maintain the DDEC oncogenic state. Furthermore, treatment with clinical-grade SMARCA4 and/or SMARCA2 ATPase inhibitors markedly attenuates DDEC cell proliferation and tumor growth in vivo and synergizes with carboplatin-based chemotherapy to extend survival. These findings reveal the oncogenic contributions of shifted mSWI/SNF family complex stoichiometry and resulting gene-regulatory dysregulation and suggest therapeutic utility of mSWI/SNF small molecule inhibitors in DDEC/UECs and other cBAF-disrupted cancer types.

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Fig. 1: ARID1A/ARID1AB dual-deficient endometrial tumors exhibit cBAF loss and increased abundance of ncBAF and PBAF complex components.
Fig. 2: Canonical BAF reassembly controls genome-wide redistribution of mSWI/SNF family complexes in DDEC cells.
Fig. 3: ARID1A/B-mediated mSWI/SNF complex reshuffling underlies altered gene regulation in DDEC cell lines and primary tumors.
Fig. 4: ARID1A and ARID1B paralogs mediate both shared and distinct gene-regulatory pathways in DDEC cell lines and primary tumors.
Fig. 5: Dual ARID1 paralog-deficient DDEC cells are sensitive to genetic disruption of ncBAF and PBAF components.
Fig. 6: Small molecule-mediated disruption of mSWI/SNF complexes attenuates oncogenic chromatin regulation and cell proliferation.
Fig. 7: Pharmacological disruption of residual mSWI/SNF complex activities attenuates DDEC tumor growth in vivo.

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Data availability

All sequencing raw and processed data are available in the Gene Expression Omnibus database under the accession no. GSE268960 (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE268960) or in the European Genome–phenome Archive under accession no. EGAS50000001004 (http://www.ega-archive.org/datasets/) All raw proteomics and MS datasets have been deposited to ProteomeXchange via PRIDE database under accession no. PXD058236. Source data are provided with this paper.

Code availability

No new code was generated for this work; all analyses have been performed according to the details described in Methods (‘RNA-seq data analysis’, ‘ATAC–seq data analysis’, ‘ChIP–seq data analysis’, ‘TMT–MS data analysis’ and ‘Statistics and reproducibility’) using available software packages.

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Acknowledgements

We thank all the members of C.K.’s laboratory and Y.W.’s and D.G.H.’s laboratories for assistance and discussion. Specifically, we thank S. Jain for assistance with ARID1A PiggyBac construct cloning and E. Li for isogenic cell line generation, as well as C. Young Shin and L. Hoang for assistance with DDEC microdissection. We also thank Z. Herbert, M. Sullivan and R. Garuti of the DFCI Molecular Biology Core Facility for help with high-throughput sequencing. J.S.L. is supported by the National Institutes of Health (NIH) Reproductive Scientist Development Program (grant no. K12-HD000849-37) and the GOG Foundation. This work was supported in part by an NIH DP2 New Innovator Award (to C.K.) and the Howard Hughes Medical Institute, Canadian Institute of Health Research (grant nos. PJT-462168 and PJT-197923 to Y.W.), Terry Fox New Frontiers Program Project Grants (nos. 1116 to Y.W. and 1082 to D.G.H). Y.W. is a recipient of the North Family Health Research Award. D.G.H. is supported by a Canada Research Chair in Molecular and Genomic Pathology. We also appreciate the generous support from the British Columbia Cancer Foundation and the VGH and UBC Hospital Foundation.

Author information

Author notes

  1. These authors contributed equally: Grace D. Xu, Alexander W. Ying, Yemin Wang.

Authors and Affiliations

  1. Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

    Jessica D. St. Laurent, Grace D. Xu, Alexander W. Ying, Ajinkya Patil, Kasey S. Cervantes, Akshay Sankar, Daniel D. Samé Guerra, Dana S. Neel & Cigall Kadoch

  2. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Jessica D. St. Laurent, Grace D. Xu, Alexander W. Ying, Ajinkya Patil, Kasey S. Cervantes, Akshay Sankar, Daniel D. Samé Guerra & Cigall Kadoch

  3. Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women’s Hospital and Harvard Medical School Boston, Boston, MA, USA

    Jessica D. St. Laurent

  4. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada

    Bengul Gokbayrak, Shary Chen, David G. Hunstman & Yemin Wang

  5. Department of Cell Biology, Harvard Medical School, Boston, MA, USA

    Joao A. Paulo & Steven P. Gygi

  6. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    William W. Feng

  7. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA

    Jun Qi

  8. Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Jason L. Hornick & David L. Kolin

  9. Howard Hughes Medical Institute, Chevy Chase, MD, USA

    Cigall Kadoch

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Contributions

J.S.L.: conceptualization, methodology, validation, formal analysis, investigation, data curation, writing, visualization and project administration. G.X., A.P., D.S.G., S.C., W.W.F., D.S.N. and B.G.: methodology, validation, formal analysis and data curation. A.W.Y., K.S.C. and A.S.: formal analysis, data curation, visualization and methodology. J.A.P.: methodology, validation, formal analysis, software and data curation. J.Q. and S.P.G.: resources. J.L.H.: data curation and resources. D.J.K.: methodology, investigation, analysis, data curation, resources and manuscript editing. Y.W.: methodology, validation, formal analysis, investigation, data curation, supervision, conceptualization, cell line-screening efforts, manuscript editing, project administration and funding acquisition. D.G.H.: resources, supervision and funding acquisition. C.K.: conceptualization, methodology, investigation, resources, data curation, writing, visualization, supervision, project administration and funding acquisition.

Corresponding author

Correspondence to Cigall Kadoch.

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Competing interests

C.K. is the Scientific Founder, Scientific Advisor to the Board of Directors, Scientific Advisory Board member, shareholder and consultant for Foghorn Therapeutics, Inc., serves on the Scientific Advisory Board of Nereid Therapeutics and is a consultant for Google Ventures. C.K. is also a member of the Molecular Cell and Cell Chemical Biology editorial boards. J.S.L is a shareholder for AI Proteins Inc. The other authors declare no competing interests.

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Extended data

Extended Data Fig. 1 mSWI/SNF gene mutations in dedifferentiated endometrial carcinomas.

A. Summary of whole-exome sequencing profiling of uterine dedifferentiated carcinomas (GENIE cohort, n = 22 cases), indicating mutation frequencies and type of mSWI/SNF, POLE, TP53, and other gene mutations. B. Summary of whole-exome sequencing profiling of endometrial/ovarian dedifferentiated carcinomas (Dana Farber dataset; n = 35 cases), indicating mutation frequencies and type of mSWI/SNF, POLE, TP53, and other genes. C. Summary of mutations in TCGA (n = 515 cases; serous/mixed/endometrioid carcinoma). Features are indicated in legend; Tumor type, tumor grade, mutation type and histology are indicated. D. Pie chart showing breakdown of mSWI/SNF gene mutations in DDEC cases from DFCI, Coatham et al., and TCGA. E. Mutual exclusivity analyses performed for mSWI/SNF, POLE, and TP53 on TCGA dataset of serous/mixed/endometrioid dedifferentiated carcinomas. F. Mutational characteristics for endometrial carcinoma cell lines used in this study. mSWI/SNF and top-mutated genes are shown (CCLE). *indicates damaging mutations. G. Immunoblot performed on nuclear extract (input) and IgG and anti-SMARCA4 immunoprecipitation from VOA1066 cells. mSWI/SNF components and TBP are shown. H. TMT-MS shown for SMARCA4 IP (and IgG control IP) in VOA1066 cells. I, J. Summary of n = 75 DDEC cases analyzed by IHC, indicating positive/negative protein staining status of ARID1A, ARID1B, SMARCA4, SMARCA2, and SMARCB1. K. SMARCA4 IHC performed on n = 3 ARID1A/ARID1B dual-mutated DDEC cases. Undifferentiated and well-differentiated compartments are indicated.

Source data

Extended Data Fig. 2 cBAF reassembly controls genome-wide redistribution of mSWI/SNF distribution and chromatin accessibility in DDEC cells.

A. Density sedimentation analyses performed on AN3CA ARID1A/B dual-deficient cells in +Dox (ARID1A rescue) conditions using 10-30% glycerol gradients. Immunoblot for selected mSWI/SNF subunits are shown; -Dox pair shown in Fig. 1e. B. PCA plot showing -/+ Dox (ARID1A rescue) conditions in AN3CA and VOA1066 cells. C. Volcano plots showing proteins (peptide signal) significantly increased and decreased upon rescue with ARID1A in AN3CA and VOA cell line systems. mSWI/SNF complex components are highlighted. D. Clustered heatmap demonstrating logFC of TMT mass-spectrometry signal in AN3CA and VOA1066 cells by subunit. E. Immunofluorescence imaging for pan-cytokeratin (green) with DAPI counterstain in both DDEC cell lines in -/+ dox conditions; scale bar= 20um, Dox treatment of 72 h, representative of n = 3 experimental replicates. F. Colony formation assays performed in AN3CA and VOA1066 cell lines following 14 days of Dox treatment (ARID1A rescue). G. Quantification of colony formation assays shown in (F), p-values determined with two-tailed Students t-test, error bars represent mean ± S.E.M. H. Bar graphs depicting number of peaks across antibodies profiled in ChIP-seq experiments. Venn diagrams depicting BRD9-GLTSCR1 (ncBAF) merged peaks in -/+ ARID1A rescue conditions in AN3CA and VOA1066 cell lines. I. Distance-to-TSS stacked bar graphs indicating peak localization for gained, lost, and retained SMARCA4 sites. J. HOMER motif analyses performed over gained and lost SMARCA4 sites in VOA1066 cells. K. PCA plot performed on ATAC–seq (broad peaks) datasets in -/+ Dox (ARID1A rescue) conditions in AN3CA and VOA1066 cells. L. Bar graphs depicting number of ATAC-seq peaks in AN3CA and VOA1066 cells in both conditions. M. Heatmaps reflecting ChIP-seq for GLTSCR1 and BRD9 as well as ATAC-seq in VOA1066 over ATAC-seq sites. Gained, lost and retained peak sets are indicated. N. Top, Overlap between de novo gained ARID1A peaks and BRD9/GLTSCR1 peaks prior to ARID1A restoration. Bottom, pie charts reflecting percent of ncBAF target sites replaced by cBAF following ARID1A restoration. O. Metaplot showing altered PBRM1 occupancy over TSS sites (top 20% expressed genes) in -/+ dox conditions. P. PBRM1 peaks in VOA1066 cells in -/+ dox conditions.

Source Data

Extended Data Fig. 3 Gene regulatory impact of cBAF restoration in DDEC cell lines and primary tumors.

A. Immunoblot for indicated mSWI/SNF components following ARID1A restoration (72 h). B. PCA plots performed on RNA-seq in AN3CA and VOA1066 cell lines following ARID1A restoration (n = 3 experimental replicates). C. Heatmaps indicating clustering of -Dox and +Dox (+HA-ARID1) conditions. D. GSEA analyses performed on AN3CA and VOA cells (ARID1A rescue/no rescue); NES, Normalized Enrichment Score. E. Clustered heatmap indicating genes up and downregulated following ARID1A rescue. F. Venn diagrams indicating cell line-specific and shared up- and down-regulated genes upon ARID1A rescue. G. Volcano plots showing up- (red) and down- (blue) regulated proteins (by TMT-MS) following 72 h of ARID1A restoration in AN3CA and VOA1066 DDEC cell lines. H. Representative ChIP-seq and ATAC-seq tracks at the CDH1, CLDN4, TONSL, and BRCA2 gene loci with corresponding bar graphs depicting gene expression (RNA-seq).

Source data

Extended Data Fig. 4 Concordant and distinct impacts of ARID1A, ARID1B, or dual paralog restoration in DDEC cell lines.

A. Immunoblot for indicated mSWI/SNF components following ARID1A, ARID1B or dual ARID1A/B restoration (72 h). B. Bar graphs indicating quantitative densitometry of blots in (I). C. Venn diagrams indicating overlap of downregulated genes (left) and sites with decreased accessibility (right) following ARID1A, ARID1B or ARID1A/B dual rescue. D. GSEA (C2 gene set) performed on AN3CA cells with ARID1A, ARID1B or dual paralog rescue relative to no rescue (-Dox) in AN3CA cells. E. Z-score heatmap indicating genes upregulated, downregulated and corresponding genes in undifferentiated (UD) and well-differentiated (WD) primary tumor compartments. F. Hallmark GSEA in AN3CA, VOA1066 cell lines following ARID1A rescue (relative to - Dox) and DDEC UD tumor compartment, normal endometrium relative to DDEC WD tumor compartment (patient); NES, Normalized Enrichment Score.

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Extended Data Fig. 5 Cell proliferation assays and CRISPR screening in cBAF-disrupted endometrial cell lines.

A. Colony formation assays performed on AN3CA cells bearing shRNAs targeting either BRD9 or ARID2. B. Immunoblot for ARID2, BRD9 and GAPDH in VOA1066 cells treated with indicated shRNA conditions. C. Bar graph depicting AUC values in indicated conditions in VOA1066 colony formation assays. D. Immunoblot for shRNA-mediated suppression of subunits indicated in AN3CA cells. E. Bar graph depicting AUC values in indicated conditions in AN3CA colony formation assays. F. Normalized read counts from genome-scale CRISPR screen (TKOv3 library). G. Box and whisker plots indicating impact across gene sets indicated on X-axis. H. Colony formation assays performed on HEC1B cells and HEC1B cells with ARID1B KO (ARID1B-BKO) treated with the indicated sgRNAs. I. Quantification of colony formation assays from (H) (relative confluency) at Day 10 post infection. J. Colony formation assays performed on HEC1B cells and HEC1B cells with ARID1B KO (ARID1B-BKO) treated with the indicated sgRNAs. K. Quantification of colony formation assays from (J) (relative confluency) at Day 10 post infection. L. Venn diagram depicting overlap between HEC1B ARID1B KO-specific dependencies and genes downregulated by ARID1 paralog restoration in AN3CA cell lines. p-values determined with two-tailed Students t-test for C, E, I and K. Error bars represent mean ± S.E.M.

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Extended Data Fig. 6 SMARCA4/2 ATPase inhibition and BRD9 degradation attenuate oncogenic gene regulation and proliferation in DDEC cells.

A. Cell proliferation measurements for VOA1066 cells upon treatment with either Cmp14 or dBRD9-A, compared to DMSO control. n = 3 experimental replicates; Significance values are indicated. B. Principal component analysis (PCA) performed on RNA-seq in VOA1066 and AN3CA cells in conditions indicated. C. Volcano plots indicating up- (red) and down- (blue) regulated genes upon either Cmp14 or dBRD9-A in VOA1066 cells; 72 h treatment. D. GSEA Hallmark performed on RNA-seq profiles in VOA1066 cells treated with Cmp14 and dBRD9-A, relative to DMSO. E. GSEA C2 gene set analysis performed in AN3CA cells treated with the indicated conditions. F. Venn diagram indicating overlap of upregulated genes (logFC>1; p < 0.01) in Cmp14 and dBRD9-A conditions in VOA1066 cells. G. Venn diagram indicated overlap of downregulated (top) and upregulated (bottom) genes (logFC>1; p < 0.01) in AN3CA cells. H. Representative ChIP-seq and ATAC-seq tracks at the GDF15 and EMP1 loci. I. PCA performed on ATAC-seq data in AN3CA and VOA1066 cells. J. Venn diagrams showing overlap of ATAC-seq peaks in AN3CA and VOA1066 cells in conditions indicated. K. HOMER motif analysis over sites with retained acccessibility (no change) in AN3CA and VOA1066 cells with dBRD9-A conditions. L. Venn diagrams indicating overlap between accessible peaks (ATAC-seq) in DMSO and Cmp14 conditions in each cell line. M. Homer motif analyses over sites with lost accessibility upon Cmp14 treatment. N. GSEA C2 gene set analysis of genes with altered accessibility withiin 2kB in AN3CA cells treated with either Cmp14 or dBRD9-A. O. Graph indicating relative confluency of HEC1B and HEC1B ARID1B KO cells across concentrations of FHD-286. P. Colony formation assays performed on HEC1B and HEC1B ARID1B KO cells treated with FHD-286 across concentrations indicated.

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Extended Data Fig. 7 mSWI/SNF pharmacologic inhibition attenuates DDEC tumor growth in vivo.

A. H&E and IHC for ARID1A, ARID1B, SMARCA4 and SMARCA2 in the XVOA14590 PDX model system; scale bars 200um. B. Individual mouse tumor volume measurements (mm3) in XVOA14590 PDX model treated with either Cmp14 or dBRD9-A. C. Representative tumor images for XVOA14590 PDX model treated with vehicle control, Cmp14, or dBRD9-A; tumors isolated at Day 16, end of study. D. Immunoblot performed on whole-cell extracts for BRD9, CRBN and beta-actin in XVOA14590 PDX treated with dBRD9-A confirming degradation relative to vehicle. E. PCA analysis performed on RNA-seq profiles derived from n = 5 tumors in each condition indicated. F. Volcano and dot plots representing differentially expressed genes in Cmp14 vs DMSO cell lines (left) and dBRD9-A treated cells (right). G. GSEA Hallmark analyses performed on n = 6 primary tumors from XVOA14590 at Day 16 post treatment in vivo. H. Tumor weight measurements (g) for VOA1066 CDX treated with either Cmp14 (top) or FHD-286 (bottom). I. (Left) Cell proliferation experiments of VOA, RL95-2 and SNGM cells (by % confluency) using single-agent and FHD-286 and carboplatin combination. (Right) D-R-(LOWE) synergy plots using Combenefit studies performed in 2D culture. J. Percent change in body weight for XVOA14590 PDX model over days of treatment with single-agent and FHD-286 and carboplatin combinations. K. Individual mouse tumor volume measurements (mm3) in VOA1066 CDX model treated with vehicle, single-agent FHD-286, carboplatin, or combination FHD-286+carboplatin.

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Supplementary information

Supplementary Information (download PDF )

Supplementary Note and Tables 1–8.

Reporting Summary (download PDF )

Supplementary Tables (download XLSX )

Supplementary Table 1 Data and calculations for all TCGA, DFCI, MSKCC endometrial carcinoma cases used in IHC. Supplementary Table 2 Features of DDEC cell lines used in the study. Supplementary Table 3 TMT–MS analysis for SMARCA4-bound complexes in VOA1066 cells. Supplementary Table 4 TMT–MS analysis for AN3CA and VOA1066 cell lines ± ARID1A WT rescue (+Dox). Supplementary Table 5 Clinicopathological information of patient samples used in LCM experiments and RNA-seq. Supplementary Table 6 Genome-scale CRISPR screening in HEC1B WT and ARID1A/B KO conditions. Supplementary Table 7 Recombinant DNA constructs utilized in this study. Supplementary Table 8 Antibodies used in this study for various methods.

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Source Data Figs. 1, 2 and 5–7 and Extended Data Figs. 2, 4 and 5–7 (download XLSX )

Statistical source data supporting Figs. 1d,h, 2f, 5b, 6b, 7b,c,f,g,i,j and Extended Data Figs. 2g, 4b, 5b,c,e,i,k, 6a,j,o and 7h,i,k.

Source Data Figs. 1, 2, 4 and 5 and Extended Data Figs. 1–5 and 7 (download PDF )

Unprocessed western blots and/or gels supporting Figs. 1c,e, 2b,c, 4b and 5a,c and Extended Data Figs. 1g, 2a, 3a, 4a, 5b,d and 7d.

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St. Laurent, J.D., Xu, G.D., Ying, A.W. et al. Shifted assembly and function of mSWI/SNF family subcomplexes underlie targetable dependencies in dedifferentiated endometrial carcinomas. Nat Genet 57, 2743–2755 (2025). https://doi.org/10.1038/s41588-025-02333-9

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