Dynamic Plasticity Systems Direct Early Adaptation to Treatment in Neuroblastoma

In paediatric cancers like neuroblastoma, limited genetic diversity emphasizes the role of phenotypic heterogeneity in driving malignancy. We investigated this phenomenon using experimental evolution and single-cell techniques in neuroblastoma preclinical models. Our findings reveal that neuroblastoma cells navigate multistable phenotypic landscapes, named plasticity systems. These finely regulate their topology and dynamics enabling tolerance, persistence, and regrowth in response to treatment. While preferential killing of adrenergic cells (ADRN), notably under cisplatin treatment, enriches drug-tolerant persister (DTP) populations with mesenchymal (MES) properties, we also observed phenotypic transitions contributing to DTP entry and exit. Additionally, single-cell-derived clone experiments unveiled a spectrum of heritable plasticity traits linked to functional properties, influencing DTP behaviour. Mathematical modelling supports the critical role of all cell phenotypes in evolutionary adaptation. Collectively, our study depicts plasticity systems as key early cancer drivers of adaptive evolution in neuroblastoma through regulating the multistability and dynamics of phenotypic landscapes. These insights underscore the necessity of decoding plasticity for advancing long-term therapeutic effectiveness.

在神经母细胞瘤等儿童恶性肿瘤中，有限的遗传多样性凸显了表型异质性在驱动肿瘤恶性进程中的核心作用。本研究借助实验进化技术与单细胞技术，在神经母细胞瘤临床前模型中对该现象开展了系统性探究。研究结果显示，神经母细胞瘤细胞可在被命名为可塑性系统（plasticity systems）的多稳态表型景观中实现表型动态调控；该系统可精细调控自身的拓扑结构与动力学特征，使肿瘤细胞能够在治疗压力下产生治疗耐受、持续存活并发生复发再增殖。尽管顺铂（cisplatin）处理下对肾上腺素能细胞（adrenergic cells，ADRN）的优先杀伤，会富集具有间质细胞（mesenchymal，MES）特性的耐药耐受残留细胞（drug-tolerant persister，DTP）群，但我们同时也观察到参与DTP细胞形成与消退的表型转换过程。此外，单细胞来源克隆实验揭示了一系列与功能特性相关的可遗传性可塑性特征，这些特征会对DTP细胞的行为产生调控影响。数学建模（mathematical modelling）结果证实了所有细胞表型在肿瘤进化适应过程中的关键作用。综上，本研究将可塑性系统（plasticity systems）刻画为神经母细胞瘤适应性进化的核心早期驱动因素，其通过调控表型景观的多稳态性与动力学特征发挥功能。这些研究结果凸显了解析肿瘤可塑性对于提升长期治疗效果的必要性。