Similar Datasets
Project description:Tumor cell heterogeneity defines therapy responsiveness in neuroblastoma (NB), a cancer derived from neural crest cells. NB consists of two primary subtypes: adrenergic and mesenchymal. Adrenergic traits predominate in NB tumors, while mesenchymal features becomes enriched post-chemotherapy or after relapse. The interconversion between these subtypes contributes to NB lineage plasticity, but the underlying mechanisms driving this phenotypic switching remain unclear. Here, we demonstrate that SWI/SNF chromatin remodeling complex ATPases are essential in establishing an mesenchymal gene-permissive chromatin state in adrenergic-type NB, facilitating lineage plasticity. Targeting SWI/SNF ATPases with SMARCA2/4 dual degraders effectively inhibits NB cell proliferation, invasion, and notably, cellular plasticity, thereby preventing chemotherapy resistance. Mechanistically, depletion of SWI/SNF ATPases compacts cis-regulatory elements, diminishes enhancer activity, and displaces core transcription factors (MYCN, HAND2, PHOX2B, and GATA3) from DNA, thereby suppressing transcriptional programs associated with plasticity. These findings underscore the pivotal role of SWI/SNF ATPases in driving intrinsic plasticity and therapy resistance in neuroblastoma, highlighting an epigenetic target for combinational treatments in this cancer.
| S-EPMC11480351 | biostudies-literature
Project description:Tumor cell heterogeneity defines therapy responsiveness in neuroblastoma (NB), a cancer derived from immature nerve cells which consists of two primary subtypes: adrenergic and mesenchymal. Adrenergic traits predominate in NB tumors, while mesenchymal features becomes enriched post-chemotherapy or after relapse. The interconversion between these subtypes contributes to NB lineage plasticity, but the underlying mechanisms driving this phenotypic switching remain unclear. Here, we demonstrate that SWI/SNF chromatin remodeling complex ATPases are essential in establishing an mesenchymal gene-permissive chromatin state in adrenergic-type NB, facilitating lineage plasticity. Targeting SWI/SNF ATPases with SMARCA2/4 dual degraders effectively inhibits NB cell proliferation, invasion, and notably, cellular plasticity, thereby preventing chemotherapy resistance. Mechanistically, depletion of SWI/SNF ATPases compacts cis-regulatory elements, diminishes enhancer activity, and displaces core transcription factors (MYCN, HAND2, PHOX2B, and GATA3) from DNA, thereby suppressing transcriptional programs associated with plasticity. These findings underscore the pivotal role of SWI/SNF ATPases in driving intrinsic plasticity and therapy resistance in neuroblastoma, highlighting an epigenetic target for combinational treatments in this cancer.
| S-SCDT-10_1038-S44318-024-00206-1 | biostudies-other
Project description:Targeting SWI/SNF ATPases reduces neuroblastoma cell plasticity
| PRJNA1004275 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2021-10-28 | GSE171592 | GEO
Project description:Neuroblastoma (NB) comprises mesenchymal (MES) and adrenergic (ADRN) subtypes, and the cell identity is determined by core transcription factors (TFs). However, the binding mechanism of these TFs to DNA and the epigenetic mechanisms governing NB plasticity remain unclear. In this study, we investigated the impact of targeting SWI/SNF ATPases with SMARCA2/4 dual degraders on NB cells. Our results revealed that depletion of SWI/SNF ATPases compacted cis-regulatory elements, diminished enhancer activity, and displaced core TFs (MYCN, HAND2, PHOX2B, and GATA3) from DNA, suppressing transcriptional programs linked to plasticity and invasiveness. These findings underscore the pivotal role of SWI/SNF ATPases in driving NB progression, positioning them as promising therapeutic targets.
2024-08-28 | GSE240724 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-04-16 | GSE229454 | GEO
Project description:Neuroblastoma (NB) comprises mesenchymal (MES) and adrenergic (ADRN) subtypes, and the cell identity is determined by core transcription factors (TFs). However, the binding mechanism of these TFs to DNA and the epigenetic mechanisms governing NB plasticity remain unclear. In this study, we investigated the impact of targeting SWI/SNF ATPases with SMARCA2/4 dual degraders on NB cells. Our results revealed that depletion of SWI/SNF ATPases compacted cis-regulatory elements, diminished enhancer activity, and displaced core TFs (MYCN, HAND2, PHOX2B, and GATA3) from DNA, suppressing transcriptional programs linked to plasticity and invasiveness. These findings underscore the pivotal role of SWI/SNF ATPases in driving NB progression, positioning them as promising therapeutic targets.
2024-08-28 | GSE240589 | GEO
Project description:Neuroblastoma (NB) comprises mesenchymal (MES) and adrenergic (ADRN) subtypes, and the cell identity is determined by core transcription factors (TFs). However, the binding mechanism of these TFs to DNA and the epigenetic mechanisms governing NB plasticity remain unclear. In this study, we investigated the impact of targeting SWI/SNF ATPases with SMARCA2/4 dual degraders on NB cells. Our results revealed that depletion of SWI/SNF ATPases compacted cis-regulatory elements, diminished enhancer activity, and displaced core TFs (MYCN, HAND2, PHOX2B, and GATA3) from DNA, suppressing transcriptional programs linked to plasticity and invasiveness. These findings underscore the pivotal role of SWI/SNF ATPases in driving NB progression, positioning them as promising therapeutic targets.
2024-08-28 | GSE240588 | GEO
Project description:Neuroblastoma (NB) comprises mesenchymal (MES) and adrenergic (ADRN) subtypes, and the cell identity is determined by core transcription factors (TFs). However, the binding mechanism of these TFs to DNA and the epigenetic mechanisms governing NB plasticity remain unclear. In this study, we investigated the impact of targeting SWI/SNF ATPases with SMARCA2/4 dual degraders on NB cells. Our results revealed that depletion of SWI/SNF ATPases compacted cis-regulatory elements, diminished enhancer activity, and displaced core TFs (MYCN, HAND2, PHOX2B, and GATA3) from DNA, suppressing transcriptional programs linked to plasticity and invasiveness. These findings underscore the pivotal role of SWI/SNF ATPases in driving NB progression, positioning them as promising therapeutic targets.
2024-08-28 | GSE240590 | GEO
Project description:The switch/sucrose non-fermentable (SWI/SNF) complex has a crucial role in chromatin remodelling1 and is altered in over 20% of cancers2,3. Here we developed a proteolysis-targeting chimera (PROTAC) degrader of the SWI/SNF ATPase subunits, SMARCA2 and SMARCA4, called AU-15330. Androgen receptor (AR)+ forkhead box A1 (FOXA1)+ prostate cancer cells are exquisitely sensitive to dual SMARCA2 and SMARCA4 degradation relative to normal and other cancer cell lines. SWI/SNF ATPase degradation rapidly compacts cis-regulatory elements bound by transcription factors that drive prostate cancer cell proliferation, namely AR, FOXA1, ERG and MYC, which dislodges them from chromatin, disables their core enhancer circuitry, and abolishes the downstream oncogenic gene programs. SWI/SNF ATPase degradation also disrupts super-enhancer and promoter looping interactions that wire supra-physiologic expression of the AR, FOXA1 and MYC oncogenes themselves. AU-15330 induces potent inhibition of tumour growth in xenograft models of prostate cancer and synergizes with the AR antagonist enzalutamide, even inducing disease remission in castration-resistant prostate cancer (CRPC) models without toxicity. Thus, impeding SWI/SNF-mediated enhancer accessibility represents a promising therapeutic approach for enhancer-addicted cancers.
| S-EPMC8770127 | biostudies-literature