TGF-β-Induced Transcription Sustains Amoeboid Melanoma Migration and Dissemination.
TGF-β-Induced Transcription Sustains Amoeboid Melanoma Migration and Dissemination.
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DOI：
10.1016/j.cub.2015.09.054
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发表时间：
2015-11-16
期刊：
影响因子：
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通讯作者：
Sanz-Moreno V
中科院分区：
文献类型：
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作者：
Cantelli G;Orgaz JL;Rodriguez-Hernandez I;Karagiannis P;Maiques O;Matias-Guiu X;Nestle FO;Marti RM;Karagiannis SN;Sanz-Moreno V
细胞迁移是癌细胞转移扩散的基础，在肿瘤侵袭前沿的快速“阿米巴”迁移是由高水平的肌球蛋白收缩控制的。阿米巴迁移如何由细胞外信号调节，并随着时间的推移由转录变化维持，目前还不完全清楚。转化生长因子β(转化生长因子-β)具有促进上皮细胞向间充质细胞转化和促进肿瘤转移的作用，但黑素细胞是胚胎发育过程中经历过细胞间充质转化的神经脊衍生物。令人惊讶的是，我们发现在黑色素瘤中，转化生长因子-β促进变形体特征，如细胞圆形、膜起泡、高水平的收缩和增加侵袭性。利用全基因组转录组学，我们发现阿米巴样黑色素瘤细胞富含转化生长因子-β驱动的信号。我们观察到，在转化生长因子-β的下游，Smad2及其接头CITED1通过调节激活收缩力量的关键基因的表达来控制变形虫的行为。此外，CITED1在黑色素瘤进展过程中高度上调，其高表达与预后不良有关。在16个黑色素瘤细胞系、小鼠黑色素瘤异种移植瘤和47例人类黑色素瘤患者中，CITED1与收缩圆形的阿米巴表型偶联。它在病变的侵袭性前沿也有丰富的表达。在功能上，我们展示了转化生长因子-β-Smad2-CITED1轴如何促进与进展相关的不同步骤：黑色素瘤从角质形成细胞分离，2D和3D迁移，附着内皮细胞，以及在体内肺转移瘤的初始定植和生长。我们提出了一种新的机制，即转化生长因子-β诱导的转录维持黑色素瘤细胞肌动球蛋白的力量，从而促进黑色素瘤的进展，而不依赖于肌动蛋白。转化生长因子-β-Smad1促进黑色素瘤中的阿米巴迁移转化生长因子-β下游，适配器CITED1控制肌球蛋白收缩阿米巴功能相关的细胞系，异种移植，和患者转化生长因子-β-Smad-CITED1转录网络控制黑色素瘤转移能力坎特利等。研究发现，在黑色素瘤中，转化生长因子-β-SMAD-CITED1通过激活转录程序控制变形体行为。结果，黑色素瘤细胞从角质形成细胞中分离出来，增加了它们的侵袭能力，并有效地在肺部定植。这是转化生长因子-β的一种新功能，不依赖于上皮细胞向间充质细胞的转化。
Cell migration underlies metastatic dissemination of cancer cells, and fast “amoeboid” migration in the invasive fronts of tumors is controlled by high levels of actomyosin contractility. How amoeboid migration is regulated by extracellular signals and sustained over time by transcriptional changes is not fully understood. Transforming growth factor β (TGF-β) is well known to promote epithelial-to-mesenchymal transition (EMT) and contribute to metastasis, but melanocytes are neural crest derivatives that have undergone EMT during embryonic development. Surprisingly, we find that in melanoma, TGF-β promotes amoeboid features such as cell rounding, membrane blebbing, high levels of contractility, and increased invasion. Using genome-wide transcriptomics, we find that amoeboid melanoma cells are enriched in a TGF-β-driven signature. We observe that downstream of TGF-β, SMAD2 and its adaptor CITED1 control amoeboid behavior by regulating the expression of key genes that activate contractile forces. Moreover, CITED1 is highly upregulated during melanoma progression, and its high expression is associated with poor prognosis. CITED1 is coupled to a contractile-rounded, amoeboid phenotype in a panel of 16 melanoma cell lines, in mouse melanoma xenografts, and in 47 human melanoma patients. Its expression is also enriched in the invasive fronts of lesions. Functionally, we show how the TGF-β-SMAD2-CITED1 axis promotes different steps associated with progression: melanoma detachment from keratinocytes, 2D and 3D migration, attachment to endothelial cells, and in vivo lung metastatic initial colonization and outgrowth. We propose a novel mechanism by which TGF-β-induced transcription sustains actomyosin force in melanoma cells and thereby promotes melanoma progression independently of EMT. TGF-β-SMAD promotes amoeboid migration in melanoma Downstream of TGF-β, the adaptor CITED1 controls actomyosin contractility Amoeboid features correlate with CITED1 levels in cell lines, xenografts, and patients TGF-β-SMAD-CITED1 transcriptional network controls melanoma metastatic ability Cantelli et al. find that, in melanoma, TGF-β-SMAD-CITED1 controls amoeboid behavior through activation of a transcriptional program. As a result, melanoma cells detach from keratinocytes, increase their invasive potential, and efficiently colonize the lung. This is a new function of TGF-β, independent of epithelial-to-mesenchymal transition.