神经母细胞瘤（NB）是一种异质性胚胎恶性肿瘤，也是婴儿期最致命的肿瘤。这是一种复杂的疾病，可能导致不同的临床结果。在一些儿童中，肿瘤会自发消退。其他人对现有治疗反应良好。但对于约占所有患者 40% 的高危人群来说，尽管在基础和临床研究方面进行了合作，但预后仍然很糟糕。虽然其确切的细胞起源仍存在争议，但 NB 被认为源自神经嵴细胞谱系，包括多能雪旺细胞前体 (SCP)，其分化为交感肾上腺细胞状态，最终产生嗜铬细胞和交感母细胞。为了了解神经母细胞瘤细胞状态，我们使用单细胞多组学对人类肿瘤样本进行了单倍型特异性分析，包括对分选的单细胞进行联合 DNA/RNA 测序 (DNTR-seq)。还使用免疫荧光染色和荧光原位杂交 (FISH) 对样品进行了评估。除了肾上腺素能肿瘤细胞之外，我们还鉴定了非整倍体 SCP 样细胞的亚群，其特征是克隆扩增、全染色体 17 增益以及增殖表达程序、细胞凋亡和非免疫调节表型。非整倍体癌前 SCP 样细胞代表了 NB 的一个新特征。遗传证据和肿瘤系统发育表明，这些克隆和恶性肾上腺素细胞群起源于迁移神经嵴或SCP起源的非整倍体倾向细胞，然后谱系定型为交感肾上腺细胞状态。我们的研究结果扩大了 NB 细胞状态的表型谱。考虑到 SCP 在发育过程中的多能性，我们认为胎儿 SCP 的转化可能代表了 NB 中以 17 号染色体畸变为特征元素的肿瘤发生的一种可能机制。© 2024。作者。

Neuroblastoma (NB) is a heterogeneous embryonal malignancy and the deadliest tumor of infancy. It is a complex disease that can result in diverse clinical outcomes. In some children, tumors regress spontaneously. Others respond well to existing treatments. But for the high-risk group, which constitutes approximately 40% of all patients, the prognosis remains dire despite collaborative efforts in basic and clinical research. While its exact cellular origin is still under debate, NB is assumed to arise from the neural crest cell lineage including multipotent Schwann cell precursors (SCPs), which differentiate into sympatho-adrenal cell states eventually producing chromaffin cells and sympathoblasts.To investigate clonal development of neuroblastoma cell states, we performed haplotype-specific analysis of human tumor samples using single-cell multi-omics, including joint DNA/RNA sequencing of sorted single cells (DNTR-seq). Samples were also assessed using immunofluorescence stainings and fluorescence in-situ hybridization (FISH).Beyond adrenergic tumor cells, we identify subpopulations of aneuploid SCP-like cells, characterized by clonal expansion, whole-chromosome 17 gains, as well as expression programs of proliferation, apoptosis, and a non-immunomodulatory phenotype.Aneuploid pre-malignant SCP-like cells represent a novel feature of NB. Genetic evidence and tumor phylogeny suggest that these clones and malignant adrenergic populations originate from aneuploidy-prone cells of migrating neural crest or SCP origin, before lineage commitment to sympatho-adrenal cell states. Our findings expand the phenotypic spectrum of NB cell states. Considering the multipotency of SCPs in development, we suggest that the transformation of fetal SCPs may represent one possible mechanism of tumor initiation in NB with chromosome 17 aberrations as a characteristic element.© 2024. The Author(s).