Targeting SWI/SNF ATPases reduces cell invasiveness and plasticity in core transcription factors-addicted neuroblastoma

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. Patient-derived xenograft (PDX) NB cells exhibit intertumoral heterogeneity, comprises MES-type and ADRN-type cells. SJNBL012407_X1 is a PDX cell line, which was maintained in neural stem-cell culture media (SCM) as spheres. To investigate the impact of depleting SWI/SNF ATPases on the emergence of heterogenous NB subpopulations, we cultured the SJNBL012407_X1 cells in 10% FBS containing media overnight, then treated the cells with DMSO (as a vehicle control) or 250 nM ACBI1 (SMARCA2/4 dual degrader) for 4 days. We used single-cell RNA sequencing (scRNA-seq) to analyze the diversity of PDX cells cultured in stem cell media, FBS-containing media that treated with or without ACBI1.