Relapse rates in high-risk neuroblastoma remain exceedingly high. The malignant cells that are responsible for relapse have not been identified, and mechanisms of therapy resistance remain poorly understood. Here, we used single nucleus RNA sequencing and bulk whole genome sequencing to identify and characterize the residual malignant persister cells that survive chemotherapy from a cohort of 20 matched diagnosis and definitive surgery tumor samples from patients treated with high-risk neuroblastoma induction chemotherapy. We show that persister cells share common mechanisms of chemotherapy escape including suppression of MYCN activity and activation of NF-κB signaling, the latter is further enhanced by cell-cell communication between the malignant cells and the tumor microenvironment. Overall, our work dissects the transcriptional landscape of cellular persistence in high-risk neuroblastoma and paves the way to the development of new therapeutic strategies to prevent disease relapse.

中文翻译：

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化疗耐药的高危神经母细胞瘤持续细胞的鉴定和表征


高危神经母细胞瘤的复发率仍然非常高。尚未确定导致复发的恶性细胞，并且对治疗耐药的机制仍知之甚少。在这里，我们使用单核 RNA 测序和批量全基因组测序，从接受高风险神经母细胞瘤诱导化疗的患者的 20 个匹配的诊断和确定性手术肿瘤样本中鉴定和表征化疗后存活的残留恶性持续细胞。我们发现，持久细胞具有共同的化疗逃逸机制，包括抑制 MYCN 活性和激活 NF-κB 信号传导，后者通过恶性细胞与肿瘤微环境之间的细胞间通讯进一步增强。总的来说，我们的工作剖析了高风险神经母细胞瘤中细胞持久性的转录景观，并为开发新的治疗策略以预防疾病复发铺平了道路。