Wnt signalling is a major determinant of neuroblastoma cell lineages
Wnt signalling is a major determinant of neuroblastoma cell lineages
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DOI：
10.1101/506980
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发表时间：
2018-12
期刊：
影响因子：
--
通讯作者：
M. Szemes;A. Greenhough;K. Malik
中科院分区：
文献类型：
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作者：
M. Szemes;A. Greenhough;K. Malik
被称为第四胚层的神经嵴包括多能细胞群，其将指定不同的细胞和组织，包括颅面软骨和骨、黑素细胞、肾上腺髓质和外周神经系统。这些细胞的命运是由基因调控网络（GRNs）在神经嵴发育的各个阶段，如诱导，规范和迁移。虽然转录因子的层次结构和它们与形态发生信号通路的相互作用的一些特点，调节发展所需的活动的全部复杂性仍然是未知的。这些通路的失调可能会导致肿瘤发生，如神经母细胞瘤，一种被认为起源于神经嵴交感肾上腺谱系的经常致命的胚胎癌症。在这个概念分析中，我们利用神经母细胞瘤细胞和肿瘤的下一代测序数据来评估Wnt信号对神经嵴GRNs和神经母细胞瘤细胞谱系的可能影响。我们提供的证据表明，Wnt信号是一个主要的决定因素的监管网络，基础间充质/NCC样细胞的身份，通过PRRX 1和雅普/TAZ转录因子。此外，Wnt还可以与Hedgehog信号传导合作，沿着肾上腺素能谱系沿着驱动前神经分化程序。我们提出，阐明信号调节网络可以增强和补充GRNs在表征细胞身份，这反过来将有助于设计改进的治疗方法，适合原发性和复发性神经母细胞瘤。
The neural crest, which has been referred to as the fourth germ layer, comprises a multipotent cell population which will specify diverse cells and tissues, including craniofacial cartilage and bones, melanocytes, the adrenal medulla and the peripheral nervous system. These cell fates are known to be determined by gene regulatory networks (GRNs) acting at various stages of neural crest development, such as induction, specification, and migration. Although transcription factor hierarchies and some of their interplay with morphogenetic signalling pathways have been characterised, the full complexity of activities required for regulated development remains uncharted. Deregulation of these pathways may contribute to tumourigenesis, as in the case of neuroblastoma, a frequently lethal embryonic cancer thought to arise from the sympathoadrenal lineage of the neural crest. In this conceptual analysis, we utilise next generation sequencing data from neuroblastoma cells and tumours to evaluate the possible influences of Wnt signalling on neural crest GRNs and on neuroblastoma cell lineages. We provide evidence that Wnt signalling is a major determinant of regulatory networks that underlie mesenchymal/NCC-like cell identities through PRRX1 and YAP/TAZ transcription factors. Furthermore, Wnt may also co-operate with Hedgehog signalling in driving proneural differentiation programmes along the adrenergic lineage. We propose that elucidation of Signalling Regulatory Networks can augment and complement GRNs in characterising cell identities, which will in turn contribute to the design of improved therapeutics tailored to primary and relapsing neuroblastoma.