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Targeting SWI/SNF ATPases reduces neuroblastoma cell plasticity
Man Xu1, Jason J Hong1, Xiyuan Zhang1
1Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
Abstract:
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.
Insights
SWI/SNF chromatin remodelers drive neuroblastoma (NB) plasticity and therapy resistance. Targeting these ATPases with degraders inhibits NB growth and prevents chemotherapy resistance by suppressing plasticity-associated gene programs.
Area of Science:
- Epigenetics
- Cancer Biology
- Chromatin Remodeling
Background:
- Neuroblastoma (NB) exhibits tumor cell heterogeneity impacting therapy response.
- NB comprises adrenergic and mesenchymal subtypes, with mesenchymal features emerging post-chemotherapy.
- Lineage plasticity underlies NB subtype interconversion, but mechanisms are poorly understood.
Purpose of the Study:
- To investigate the role of SWI/SNF chromatin remodeling complex ATPases in NB lineage plasticity.
- To evaluate the therapeutic potential of targeting SWI/SNF ATPases in neuroblastoma.
Main Methods:
- Utilized SMARCA2/4 dual degraders to target SWI/SNF ATPases.
- Assessed effects on NB cell proliferation, invasion, and cellular plasticity.
- Analyzed chromatin accessibility, enhancer activity, and transcription factor binding.
Main Results:
- SWI/SNF ATPases are crucial for establishing a mesenchymal gene-permissive chromatin state in adrenergic NB.
- Targeting SWI/SNF ATPases with degraders inhibited NB proliferation, invasion, and plasticity.
- SWI/SNF ATPase depletion led to compacted chromatin, reduced enhancer activity, and displaced key transcription factors.
Conclusions:
- SWI/SNF ATPases are pivotal drivers of neuroblastoma's intrinsic plasticity and therapy resistance.
- Targeting SWI/SNF ATPases represents a promising epigenetic strategy for combination treatments in neuroblastoma.
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