Distinct SOX signature determines neuroblastoma origin and predicts clinical outcome. Distinct SOX signature determines neuroblastoma origin and predicts clinical outcome

Multimodality treatment of high-risk neuroblastoma can be effective, but up to 50% of children experience recurrent disease with fatal outcome. Extensive genetic intratumoral heterogeneity and diverse clinical outcomes pose therapeutic challenges in treating children affected by this aggressive disease. Several hypotheses have been proposed to explain the heterogeneity of neuroblastoma, including a possible origin from multipotent neural crest stem cells (NCSCs). Utilizing an in vivo mouse genetics approach, we demonstrate that lineage-restricted sympathoadrenal (SA) progenitors and not NCSCs are the cellular origin of neuroblastoma. Human neuroblastoma tissue is composed of two spatially juxtaposed cell types, neuroblasts and Schwann cells, both cell types derive from neural crest (NC) lineage. This composition mimics the architecture of sympathetic ganglions (SG) as well as of adrenal medulla at the late stage of neural crest (NC) development. Similarly to SG, SOX10 is restricted to Schwannian cells and is not present in tumorigenic neuroblasts. Transcriptional landscape of Sox genes can serve as paradigmatic model for stage identification along NC lineage development. While early multipotent NCSCs are characterized by the expression of Sox9/Sox10 transcription factors (TF), committed SA progenitor identity is defined by the presence of Sox4/Sox11 TFs. Molecularly, we show that the core transcriptional network that orchestrate neuroblastoma maintenance is highly reminiscent of the SA progenitors. Taken together, the data presented here show that neuroblastoma cells functionally resemble the committed SA progenitors, while lacking specific stem cell program. Overall design: RNA-seq of human neuroblastoma cell lines overexpress or knockdown SOX9

高危神经母细胞瘤（high-risk neuroblastoma）的多模式治疗（multimodality treatment）虽可取得一定疗效，但仍有高达50%的患儿会出现复发疾病（recurrent disease）并以致命结局（fatal outcome）告终。广泛存在的瘤内异质性（intratumoral heterogeneity）与多样化的临床结局，为治疗这类侵袭性疾病（aggressive disease）患儿带来了严峻挑战。
学界已提出多种假说以解释神经母细胞瘤的异质性，其中一种假说认为其可能起源于多能神经嵴干细胞（multipotent neural crest stem cells, NCSCs）。本研究借助体内小鼠遗传学方法（in vivo mouse genetics approach）证实，谱系限制性交感肾上腺（sympathoadrenal, SA）祖细胞而非NCSCs，才是神经母细胞瘤的细胞起源（cellular origin）。
人神经母细胞瘤组织由两种空间毗邻的细胞类型构成：成神经细胞（neuroblasts）与施万细胞（Schwann cells），二者均源自神经嵴（neural crest, NC）谱系。该组织构成模拟了神经嵴发育晚期交感神经节（sympathetic ganglions, SG）与肾上腺髓质（adrenal medulla）的结构特征。与交感神经节一致，SOX10仅表达于施万细胞，而在致瘤性成神经细胞（tumorigenic neuroblasts）中无表达。
Sox基因的转录图谱（transcriptional landscape of Sox genes）可作为神经嵴谱系发育阶段鉴定的范式模型（paradigmatic model）。早期多能NCSCs以表达Sox9/Sox10转录因子（transcription factors, TF）为特征，而定向分化的SA祖细胞则以表达Sox4/Sox11转录因子为标志。从分子层面来看，本研究显示，调控神经母细胞瘤维持（neuroblastoma maintenance）的核心转录网络与SA祖细胞高度相似。
综上，本研究数据表明，神经母细胞瘤细胞在功能上类似定向分化的SA祖细胞，却缺乏特异性干细胞程序（specific stem cell program）。整体实验设计：对过表达（overexpress）或敲低（knockdown）SOX9的人神经母细胞瘤细胞系开展RNA测序（RNA-seq）。