Institut Curie, Paris Sciences et Lettres (PSL) Research University, INSERM, U900, Mines-ParisTech, Paris, France.
Institut Cochin, Inserm U1016, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 8104, University Paris Descartes UMR-S1016, Paris, France.
Nat Genet. 2017 Sep;49(9):1408-1413. doi: 10.1038/ng.3921. Epub 2017 Jul 24.
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.
神经母细胞瘤是外周交感神经系统的肿瘤，来源于多能神经嵴细胞（NCC）。为了确定控制神经母细胞瘤基因表达程序的核心调控回路（CRC），我们建立并分析了神经母细胞瘤超级增强子景观。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；NCC 样身份，由包含 AP-1 TF 的 CRC 模块驱动；以及混合类型，在单细胞水平进一步分解。用化疗药物治疗混合类型会导致 NCC 样细胞的富集。去甲肾上腺素能模块通过 ChIP-seq 进行了验证。功能研究表明，具有去甲肾上腺素能身份的神经母细胞瘤依赖 PHOX2B，类似于谱系成瘾。大多数神经母细胞瘤原发肿瘤表达来自去甲肾上腺素能和 NCC 样模块的 TF。我们的数据表明了与神经母细胞瘤治疗策略相关的肿瘤异质性的一个以前未知的方面。
