Tumor Cell-Driven Extracellular Matrix Remodeling Drives Haptotaxis during Metastatic Progression.
Tumor Cell-Driven Extracellular Matrix Remodeling Drives Haptotaxis during Metastatic Progression.
复制标题
肿瘤细胞驱动的细胞外基质重塑在转移性过程中触觉驱动。
DOI：
10.1158/2159-8290.cd-15-1183
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发表时间：
2016-05
期刊：
影响因子：
28.2
通讯作者：
Gertler FB
中科院分区：
文献类型：
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作者：
Oudin MJ;Jonas O;Kosciuk T;Broye LC;Guido BC;Wyckoff J;Riquelme D;Lamar JM;Asokan SB;Whittaker C;Ma D;Langer R;Cima MJ;Wisinski KB;Hynes RO;Lauffenburger DA;Keely PJ;Bear JE;Gertler FB
纤维连接蛋白（FN）是肿瘤微环境的主要成分，但其在促进转移中的作用尚不完全清楚。在这里，我们表明，FN梯度引起乳腺癌细胞的定向运动，在体外和体内。FN梯度上的趋合性需要α5β1整联蛋白和肌动蛋白调节剂Mena之间的直接相互作用，并涉及局灶复合物信号传导和肿瘤细胞介导的细胞外基质（ECM）重塑的增加。与Mena相比，更高水平的促转移MenaINV同种型与α5相关，这使得肿瘤细胞能够朝向通常存在于血管周围空间和乳腺肿瘤组织外周中的高FN浓度进行3D趋触。MenaINV和FN水平在两个乳腺癌队列中相关，并且高水平的MenaINV与肿瘤复发增加以及患者存活率降低显著相关。我们的研究结果确定了一种新的肿瘤细胞内在机制，通过ECM重塑和ECM引导的定向迁移促进转移。
Fibronectin (FN) is a major component of the tumor microenvironment, but its role in promoting metastasis is incompletely understood. Here we show that FN gradients elicit directional movement of breast cancer cells, in vitro and in vivo. Haptotaxis on FN gradients requires direct interaction between α5β1 integrin and Mena, an actin regulator, and involves increases in focal complex signaling and tumor-cell-mediated extracellular matrix (ECM) remodeling. Compared to Mena, higher levels of the pro-metastatic MenaINV isoform associate with α5, which enables 3D haptotaxis of tumor cells towards the high FN concentrations typically present in perivascular space and in the periphery of breast tumor tissue. MenaINV and FN levels were correlated in two breast cancer cohorts, and high levels of MenaINV were significantly associated with increased tumor recurrence as well as decreased patient survival. Our results identify a novel tumor-cell-intrinsic mechanism that promotes metastasis through ECM remodeling and ECM guided directional migration.