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Cooperative behaviour and phenotype plasticity evolve during melanoma progression.
Pigment Cell & Melanoma Research ( IF 3.9 ) Pub Date : 2020-03-07 , DOI: 10.1111/pcmr.12873
Emily J Rowling 1 , Zsofia Miskolczi 1 , Raghavendar Nagaraju 1 , Daniel J Wilcock 1 , Ping Wang 2 , Brian Telfer 3 , Yaoyong Li 4 , Irene Lasheras-Otero 5 , Marta Redondo-Muñoz 5 , Andrew D Sharrocks 4 , Imanol Arozarena 5 , Claudia Wellbrock 1
Affiliation  

A major challenge for managing melanoma is its tumour heterogeneity based on individual co‐existing melanoma cell phenotypes. These phenotypes display variable responses to standard therapies, and they drive individual steps of melanoma progression; hence, understanding their behaviour is imperative. Melanoma phenotypes are defined by distinct transcriptional states, which relate to different melanocyte lineage development phases, ranging from a mesenchymal, neural crest‐like to a proliferative, melanocytic phenotype. It is thought that adaptive phenotype plasticity based on transcriptional reprogramming drives melanoma progression, but at which stage individual phenotypes dominate and moreover, how they interact is poorly understood. We monitored melanocytic and mesenchymal phenotypes throughout melanoma progression and detected transcriptional reprogramming at different stages, with a gain in mesenchymal traits in circulating melanoma cells (CTCs) and proliferative features in metastatic tumours. Intriguingly, we found that distinct phenotype populations interact in a cooperative manner, which generates tumours of greater “fitness,” supports CTCs and expands organotropic cues in metastases. Fibronectin, expressed in mesenchymal cells, acts as key player in cooperativity and promotes survival of melanocytic cells. Our data reveal an important role for inter‐phenotype communications at various stages of disease progression, suggesting these communications could act as therapeutic target.

中文翻译:

在黑素瘤进展过程中,合作行为和表型可塑性会发生变化。

处理黑色素瘤的主要挑战是基于个体共存的黑色素瘤细胞表型的肿瘤异质性。这些表型显示出对标准疗法的不同反应,并且它们驱动黑素瘤进展的各个步骤。因此,了解他们的行为势在必行。黑色素瘤的表型是由不同的转录状态定义的,这些转录状态与不同的黑素细胞谱系发育阶段有关,从间充质,神经neural样到增生的黑素细胞表型。据认为,基于转录重编程的适应性表型可塑性驱动黑素瘤的进展,但是在各个阶段,个体表型占主导地位,此外,人们对它们如何相互作用的了解甚少。我们在整个黑素瘤进展过程中监测了黑素细胞和间充质表型,并检测了不同阶段的转录重编程,循环黑素瘤细胞(CTC)中的间充质性状得到了提高,转移性肿瘤中的增殖特性得到了改善。有趣的是,我们发现不同的表型群体以合作方式相互作用,从而产生更大的“适应性”肿瘤,支持CTC并扩大了转移中的嗜有机性提示。在间充质细胞中表达的纤连蛋白在协同作用中起关键作用,并促进黑素细胞的存活。我们的数据揭示了在疾病进展的各个阶段表型间交流的重要作用,表明这些交流可以作为治疗靶标。在循环性黑色素瘤细胞(CTC)中具有间充质特征,在转移性肿瘤中具有增生特征。有趣的是,我们发现不同的表型群体以合作方式相互作用,从而产生更大的“适应性”肿瘤,支持CTC并扩大了转移中的嗜有机性提示。在间充质细胞中表达的纤连蛋白在协同作用中起关键作用,并促进黑素细胞的存活。我们的数据揭示了在疾病进展的各个阶段表型间交流的重要作用,表明这些交流可以作为治疗靶标。在循环性黑色素瘤细胞(CTC)中具有间充质特征,在转移性肿瘤中具有增生特征。有趣的是,我们发现不同的表型群体以合作方式相互作用,从而产生更大的“适应性”肿瘤,支持CTC并扩大了转移中的嗜有机性提示。在间充质细胞中表达的纤连蛋白在协同作用中起关键作用,并促进黑素细胞的存活。我们的数据揭示了在疾病进展的各个阶段表型间交流的重要作用,表明这些交流可以作为治疗靶标。”支持CTC并扩大转移灶中的有机提示。在间充质细胞中表达的纤连蛋白在协同作用中起关键作用,并促进黑素细胞的存活。我们的数据揭示了在疾病进展的各个阶段表型间交流的重要作用,表明这些交流可以作为治疗靶标。”支持CTC并扩大转移灶中的有机提示。在间充质细胞中表达的纤连蛋白在协同作用中起关键作用,并促进黑素细胞的存活。我们的数据揭示了在疾病进展的各个阶段表型间交流的重要作用,表明这些交流可以作为治疗靶标。
更新日期:2020-03-07
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