肿瘤细胞异质性决定了神经母细胞瘤 (NB) 的治疗反应性，神经母细胞瘤是一种源自神经嵴细胞的癌症。 NB 由两种主要亚型组成：肾上腺素能亚型和间充质亚型。肾上腺素能特征在 NB 肿瘤中占主导地位，而间质特征在化疗后或复发后变得丰富。这些亚型之间的相互转换有助于 NB 谱系可塑性，但驱动这种表型转换的潜在机制仍不清楚。在这里，我们证明 SWI/SNF 染色质重塑复合物 ATP 酶对于在肾上腺素能型 NB 中建立间充质基因允许的染色质状态至关重要，从而促进谱系可塑性。使用 SMARCA2/4 双重降解剂靶向 SWI/SNF ATP 酶可有效抑制 NB 细胞增殖、侵袭，尤其是细胞可塑性，从而防止化疗耐药。从机制上讲，SWI/SNF ATP酶的耗尽会压缩顺式调控元件，降低增强子活性，并取代DNA中的核心转录因子（MYCN、HAND2、PHOX2B和GATA3），从而抑制与可塑性相关的转录程序。这些发现强调了 SWI/SNF ATP 酶在驱动神经母细胞瘤的内在可塑性和治疗耐药性方面的关键作用，强调了这种癌症联合治疗的表观遗传靶点。© 2024。这是美国政府的作品，在美国不受版权保护；外国版权保护可能适用。

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.© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.