Nck deficiency is associated with delayed breast carcinoma progression and reduced metastasis.
Nck deficiency is associated with delayed breast carcinoma progression and reduced metastasis.
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DOI：
10.1091/mbc.e17-02-0106
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发表时间：
2017-11-15
影响因子：
3.3
通讯作者：
Rivera GM
中科院分区：
文献类型：
--
作者：
Morris DC;Popp JL;Tang LK;Gibbs HC;Schmitt E;Chaki SP;Bywaters BC;Yeh AT;Porter WW;Burghardt RC;Barhoumi R;Rivera GM
NCK通过调控CDC42和RhoA的时空激活，引导癌细胞与胶原纤维的极化相互作用，降低肌动蛋白的周转，增强MMP14在细胞表面的定位和活性，从而促进乳腺癌的进展和转移。尽管已知酪氨酸激酶非催化区(Nck)通过连接酪氨酸磷酸化和细胞骨架重塑来调节细胞的黏附和迁移，但Nck在肿瘤发生和转移中的作用尚不清楚。在此，我们报道了在乳腺癌异种移植模型中，NCK对于原发肿瘤和肺转移瘤的生长和血管形成以及向尾静脉注射癌细胞后的渗出都是必需的。我们提供的证据表明，NCK引导细胞-基质相互作用的极化，以便在三维微环境中高效迁移。我们发现，NCK通过调节侵袭足的肌动蛋白动力学，并通过引导MMP14在细胞表面的传递和积聚来促进聚焦的细胞外基质蛋白分解，从而促进乳腺癌细胞的侵袭。我们发现，NCK依赖的细胞骨架变化与增强的RhoA有关，但限制了CDC42的时空激活。结合蛋白质沉默和野生型/成分活性变异体的强制表达，我们提供了Nck是RhoA依赖的MMP14介导的乳腺癌细胞侵袭的上游调节因子的证据。通过确定NCK是乳腺癌进展和转移的重要驱动因素，这些结果为未来评估靶向NCK在侵袭性癌症中的治疗潜力奠定了基础。
Nck promotes breast carcinoma progression and metastasis by directing the polarized interaction of carcinoma cells with collagen fibrils, decreasing actin turnover, and enhancing the localization and activity of MMP14 at the cell surface through modulation of the spatiotemporal activation of Cdc42 and RhoA. Although it is known that noncatalytic region of tyrosine kinase (Nck) regulates cell adhesion and migration by bridging tyrosine phosphorylation with cytoskeletal remodeling, the role of Nck in tumorigenesis and metastasis has remained undetermined. Here we report that Nck is required for the growth and vascularization of primary tumors and lung metastases in a breast cancer xenograft model as well as extravasation following injection of carcinoma cells into the tail vein. We provide evidence that Nck directs the polarization of cell–matrix interactions for efficient migration in three-dimensional microenvironments. We show that Nck advances breast carcinoma cell invasion by regulating actin dynamics at invadopodia and enhancing focalized extracellular matrix proteolysis by directing the delivery and accumulation of MMP14 at the cell surface. We find that Nck-dependent cytoskeletal changes are mechanistically linked to enhanced RhoA but restricted spatiotemporal activation of Cdc42. Using a combination of protein silencing and forced expression of wild-type/constitutively active variants, we provide evidence that Nck is an upstream regulator of RhoA-dependent, MMP14-mediated breast carcinoma cell invasion. By identifying Nck as an important driver of breast carcinoma progression and metastasis, these results lay the groundwork for future studies assessing the therapeutic potential of targeting Nck in aggressive cancers.