The HU177 Collagen Epitope Controls Melanoma Cell Migration and Experimental Metastasis by a CDK5/YAP-Dependent Mechanism
The HU177 Collagen Epitope Controls Melanoma Cell Migration and Experimental Metastasis by a CDK5/YAP-Dependent Mechanism
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DOI：
10.1016/j.ajpath.2018.06.017
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发表时间：
2018-10-01
影响因子：
6
通讯作者：
Brooks, Peter C.
中科院分区：
文献类型：
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作者：
Caron, Jennifer M.;Han, XiangHua;Brooks, Peter C.
基质成分不仅有助于形成肿瘤如黑色素瘤的结构，而且在功能上有助于其恶性表型。因此，揭示整合肿瘤和基质细胞行为的信号通路可能为开发更有效的策略以控制肿瘤进展提供独特的机会。在这方面，细胞外基质介导的信号传导在协调肿瘤细胞和基质细胞的行为中起作用。在此，提供了靶向细胞外基质蛋白胶原蛋白（HU 177表位）的隐蔽区的证据，抑制黑色素瘤肿瘤生长和转移，并减少血管生成和这些肿瘤中表达α-SMA的基质细胞的积累。目前的研究表明，HU 177表位控制黑色素瘤细胞迁移和转移的能力取决于转录辅激活因子Yes相关蛋白（雅普）。黑色素瘤细胞与HU 177表位的相互作用通过细胞周期蛋白依赖性激酶5相关机制促进雅普的核积累。这些发现为抗HU 177抗体抑制转移的机制提供了新的见解，并揭示了HU 177表位通过调节雅普的核定位来选择性地重编程黑素瘤细胞的未知信号传导途径。这项研究有助于确定一种潜在的新的治疗策略，以控制黑色素瘤肿瘤的生长和转移，可能单独使用或与其他治疗药物联合使用。
Stromal components not only help form the structure of neoplasms such as melanomas, but they also functionally contribute to their malignant phenotype. Thus, uncovering signaling pathways that integrate the behavior of both tumor and stromaL cells may provide unique opportunities for the development of more effective strategies to control tumor progression. In this regard, extracellular matrix-mediated signaling plays a role in coordinating the behavior of both tumor and stromal cells. Here, evidence is provided that targeting a cryptic region of the extracellular matrix protein collagen (HU177 epitope) inhibits melanoma tumor growth and metastasis and reduces angiogenesis and the accumulation of alpha-SMA-expressing stromal cell in these tumors. The current study suggests that the ability of the HU177 epitope to control melanoma cell migration and metastasis depends on the transcriptional coactivator Yes-associated protein (YAP). Melanoma cell interactions with the HU177 epitope promoted nuclear accumulation of YAP by a cyclin-dependent kinase-5-associated mechanism. These findings provide new insights into the mechanism by which the anti-HU177 antibody inhibits metastasis, and uncovers an unknown signaling pathway by which the HU177 epitope selectively reprograms melanoma cells by regulating nuclear localization of YAP. This study helps to define a potential new therapeutic strategy to control melanoma tumor growth and metastasis that might be used alone or in combination with other therapeutics.