Two cell identities, noradrenergic and mesenchymal, have been characterized in neuroblastoma cell lines according to their epigenetic landscapes relying on specific circuitries of transcription factors. Yet, their relationship and relative contribution in patient tumors remain poorly defined. Here, we demonstrate that the knock-out of GATA3, but not of PHOX2A or PHOX2B, in noradrenergic cells induces a mesenchymal phenotype. Our results document spontaneous plasticity in several models between both identities and show that plasticity relies on epigenetic reprogramming. We demonstrate that an in vivo microenvironment provides a powerful pressure towards a noradrenergic identity for these models. Consistently, tumor cells with a mesenchymal identity are not detected in a series of PDX models. Further study of the intra-tumor noradrenergic heterogeneity reveals two distinct cell populations exhibiting features of chromaffin-like or sympathoblast-like cells. This work emphasizes that both external cues of the environment and intrinsic factors control plasticity and cell identity in neuroblastoma.

中文翻译：

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内在重编程潜力与微环境之间的相互作用控制神经母细胞瘤细胞的可塑性和特性

在神经母细胞瘤细胞系中，根据依赖于转录因子特定途径的表观遗传学特征，已经鉴定出两种细胞身份，即去甲肾上腺素能和间充质。然而，它们在患者肿瘤中的关系和相对贡献仍然不清楚。在这里，我们证明了在去甲肾上腺素能细胞中，GATA3的敲除而不是PHOX2A或PHOX2B的敲除诱导了间充质表型。我们的结果在两个身份之间的多个模型中记录了自发可塑性，并表明可塑性依赖于表观遗传重编程。我们证明了体内微环境为这些模型向去甲肾上腺素身份提供了强大的压力。一致地，在一系列PDX模型中未检测到具有间充质同一性的肿瘤细胞。进一步研究肿瘤内的去甲肾上腺素异质性，发现两个不同的细胞群表现出嗜铬细胞样或交感神经细胞样细胞的特征。这项工作强调环境的外部提示和内在因素都控制神经母细胞瘤的可塑性和细胞特性。