Metastasis is the major cause of cancer-related deaths. Neuroblastoma (NB), a childhood tumor has been molecularly defined at the primary cancer site, however, the bone marrow (BM) as the metastatic niche of NB is poorly characterized. Here we perform single-cell transcriptomic and epigenomic profiling of BM aspirates from 11 subjects spanning three major NB subtypes and compare these to five age-matched and metastasis-free BM, followed by in-depth single cell analyses of tissue diversity and cell-cell interactions, as well as functional validation. We show that cellular plasticity of NB tumor cells is conserved upon metastasis and tumor cell type composition is NB subtype-dependent. NB cells signal to the BM microenvironment, rewiring via macrophage mgration inhibitory factor and midkine signaling specifically monocytes, which exhibit M1 and M2 features, are marked by activation of pro- and anti-inflammatory programs, and express tumor-promoting factors, reminiscent of tumor-associated macrophages. The interactions and pathways characterized in our study provide the basis for therapeutic approaches that target tumor-to-microenvironment interactions.

转移是癌症相关死亡的主要原因。神经母细胞瘤 (NB) 是一种儿童肿瘤，已在原发癌症部位进行了分子定义，然而，作为 NB 的转移生态位的骨髓 (BM) 的特征却很差。在这里，我们对来自 11 名受试者（涵盖三种主要 NB 亚型）的 BM 抽吸物进行单细胞转录组和表观基因组分析，并将其与 5 名年龄匹配且无转移的 BM 进行比较，然后对组织多样性和细胞间进行深入的单细胞分析交互以及功能验证。我们表明，NB 肿瘤细胞的细胞可塑性在转移时是保守的，并且肿瘤细胞类型组成是 NB 亚型依赖性的。NB 细胞向 BM 微环境发出信号，通过巨噬细胞迁移抑制因子和中期因子信号传导（特别是单核细胞）重新布线，它们表现出 M1 和 M2 特征，以促炎和抗炎程序的激活为标志，并表达肿瘤促进因子，让人想起肿瘤相关的巨噬细胞。我们研究中表征的相互作用和途径为针对肿瘤与微环境相互作用的治疗方法提供了基础。