Neuroblastoma is a tumor of the peripheral sympathetic nervous system, derived from multipotent neural crest cells (NCCs). To define core regulatory circuitries (CRCs) controlling the gene expression program of neuroblastoma, we established and analyzed the neuroblastoma super-enhancer landscape. We discovered three types of identity in neuroblastoma cell lines: a sympathetic noradrenergic identity, defined by a CRC module including the PHOX2B, HAND2 and GATA3 transcription factors (TFs); an NCC-like identity, driven by a CRC module containing AP-1 TFs; and a mixed type, further deconvoluted at the single-cell level. Treatment of the mixed type with chemotherapeutic agents resulted in enrichment of NCC-like cells. The noradrenergic module was validated by ChIP-seq. Functional studies demonstrated dependency of neuroblastoma with noradrenergic identity on PHOX2B, evocative of lineage addiction. Most neuroblastoma primary tumors express TFs from the noradrenergic and NCC-like modules. Our data demonstrate a previously unknown aspect of tumor heterogeneity relevant for neuroblastoma treatment strategies.

中文翻译：

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由转录电路定义的神经母细胞瘤细胞身份的异质性。

神经母细胞瘤是一种周围交感神经系统的肿瘤，来源于多能神经嵴细胞 (NCC)。为了定义控制神经母细胞瘤基因表达程序的核心调控电路 (CRC)，我们建立并分析了神经母细胞瘤超增强子景观。我们在神经母细胞瘤细胞系中发现了三种类型的身份：交感神经去甲肾上腺素能身份，由包含 PHOX2B、HAND2 和 GATA3 转录因子 (TF) 的 CRC 模块定义；由包含 AP-1 TF 的 CRC 模块驱动的类似 NCC 的身份；和混合型，在单细胞水平上进一步去卷积。用化学治疗剂处理混合型导致NCC样细胞富集。去甲肾上腺素能模块由 ChIP-seq 验证。功能研究表明具有去甲肾上腺素能特性的神经母细胞瘤对 PHOX2B 的依赖性，引起谱系成瘾。大多数神经母细胞瘤原发性肿瘤表达来自去甲肾上腺素能和 NCC 样模块的 TF。我们的数据证明了与神经母细胞瘤治疗策略相关的肿瘤异质性的一个先前未知的方面。