Notch3 signaling-mediated melanoma-endothelial crosstalk regulates melanoma stem-like cell homeostasis and niche morphogenesis.
Notch3 signaling-mediated melanoma-endothelial crosstalk regulates melanoma stem-like cell homeostasis and niche morphogenesis.
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DOI：
10.1038/labinvest.2017.1
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发表时间：
2017-06
期刊：
影响因子：
--
通讯作者：
Alani RM
中科院分区：
文献类型：
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作者：
Hsu MY;Yang MH;Schnegg CI;Hwang S;Ryu B;Alani RM
黑色素瘤是最致命的癌症之一，这是由于其转移倾向和对当前疗法的抗性。治疗失败主要归因于肿瘤异质性，特别是具有干细胞样性质的亚群，即，黑色素瘤干细胞样细胞（MSLC）。有证据表明，MSLC表型是可塑性的，并且可以通过在适当的刺激下的表型转换（所谓的"动态干性"）由非MSLC获得。由于MSLC的表型特征和功能完整性取决于其血管生态位，因此使用二维（2D）黑素瘤-内皮共培养模型，其中MSLC生态位在体外重现，我们通过途径特异性基因表达阵列将Notch3信号通路鉴定为控制MSLC表型可塑性的微环境线索。因此，在表现出高水平内源性Notch3的黑素瘤细胞系中，慢病毒shRNA介导的Notch3敲低（KD）通过两种消耗MSLC级分导致体内致瘤性延迟/消除，这通过MSLC标志物下调（例如，CD133和CD271）;并阻碍MSLC生态位，这由减弱的肿瘤血管生成以及血管生成拟态证实。相反，Notch3 KD既不影响肿瘤生长，也不影响内源性Notch3表达相对较低的黑素瘤细胞系中的MSLC亚群。因此，Notch3信号传导可以以细胞环境依赖的方式促进MSLC可塑性和生态位形态发生。我们的研究结果说明Notch3作为一个分子开关驱动黑色素瘤异质性，并提供Notch抑制作为一个有前途的治疗选择的生物学原理。
Melanoma is among the most virulent cancers, owing to its propensity to metastasize and its resistance to current therapies. The treatment failure is largely attributed to tumor heterogeneity, particularly subpopulations possessing stem cell-like properties, i.e., melanoma stem-like cells (MSLCs). Evidence indicates that the MSLC phenotype is malleable and may be acquired by non-MSLCs through phenotypic switching upon appropriate stimuli, the so–called “dynamic stemness”. Since the phenotypic characteristics and functional integrity of MSLCs depend on their vascular niche, using a two dimensional (2D) melanoma-endothelium co-culture model, where the MSLC niche is recapitulated in vitro, we identified Notch3 signaling pathway as a micro-environmental cue governing MSLC phenotypic plasticity via pathway-specific gene expression arrays. Accordingly, lentiviral shRNA-mediated Notch3 knockdown (KD) in melanoma cell lines exhibiting high levels of endogenous Notch3 led to retarded/abolished tumorigenicity in vivo through both depleting MSLC fractions, evinced by MSLC marker down-regulation (e.g., CD133 and CD271); and impeding the MSLC niche, corroborated by the attenuated tumor angiogenesis as well as vasculogenic mimicry. In contrast, Notch3 KD affected neither tumor growth nor MSLC subsets in a melanoma cell line with relatively low endogenous Notch3 expression. Thus, Notch3 signaling may facilitate MSLC plasticity and niche morphogenesis in a cell context-dependent fashion. Our findings illustrate Notch3 as a molecular switch driving melanoma heterogeneity, and provide the biological rationale for Notch inhibition as a promising therapeutic option.