Coronin 1C promotes triple-negative breast cancer invasiveness through regulation of MT1-MMP traffic and invadopodia function
Coronin 1C promotes triple-negative breast cancer invasiveness through regulation of MT1-MMP traffic and invadopodia function
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DOI：
10.1038/s41388-018-0422-x
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发表时间：
2018-12-13
期刊：
影响因子：
8
通讯作者：
Chavrier, Philippe
中科院分区：
文献类型：
--
作者：
Castagnino, Alessia;Castro-Castro, Antonio;Chavrier, Philippe
膜型1-基质金属蛋白酶（MT1-MMP）是肿瘤侵袭转移过程中基质分解的关键酶。通过Arp2/3复合体组装分支肌动蛋白网络是MT1-MMP传输和基质降解侵入物形成所必需的。与肌动蛋白丝分支因子在癌细胞侵袭过程中侵过壁功能中的作用相比，冠状蛋白家族去分支因子在侵过壁基质重塑中的作用尚不清楚。在这里，我们研究了冠状蛋白1C对乳腺癌细胞侵袭潜力的贡献。我们报道，冠状蛋白1C的表达在侵袭性人乳腺癌中升高，与MT1-MMP的表达呈正相关，与转移风险增加有关，是乳腺癌的一个新的独立预后因素。我们提供的证据表明，与接触类似，冠状蛋白1C对于乳腺癌细胞系的浸润性形成和基质降解以及多细胞球体的3D胶原浸润是必需的。通过原位人乳腺肿瘤异种移植的活体成像，我们发现在肿瘤微环境中，冠状蛋白1C在与胶原原纤维相关的结构中积累。此外，我们确定了冠状蛋白1C在调节mt1 - mmp阳性内溶酶体的定位和运输中的作用。这些结果表明，冠状蛋白1C在乳腺癌细胞浸润性形成、MT1-MMP表面暴露和侵袭性的多方面机制中起着新的作用。
Membrane type 1-matrix metalloproteinase (MT1-MMP), a membrane-tethered protease, is key for matrix breakdown during cancer invasion and metastasis. Assembly of branched actin networks by the Arp2/3 complex is required for MT1-MMP traffic and formation of matrix-degradative invadopodia. Contrasting with the well-established role of actin filament branching factor cortactin in invadopodia function during cancer cell invasion, the contribution of coronin-family debranching factors to invadopodia-based matrix remodeling is not known. Here, we investigated the contribution of coronin 1C to the invasive potential of breast cancer cells. We report that expression of coronin 1C is elevated in invasive human breast cancers, correlates positively with MT1-MMP expression in relation with increased metastatic risk and is a new independent prognostic factor in breast cancer. We provide evidence that, akin to cortactin, coronin 1C is required for invadopodia formation and matrix degradation by breast cancer cells lines and for 3D collagen invasion by multicellular spheroids. Using intravital imaging of orthotopic human breast tumor xenografts, we find that coronin 1C accumulates in structures forming in association with collagen fibrils in the tumor microenvironment. Moreover, we establish the role of coronin 1C in the regulation of positioning and trafficking of MT1-MMP-positive endolysosomes. These results identify coronin 1C as a novel player of the multi-faceted mechanism responsible for invadopodia formation, MT1-MMP surface exposure and invasiveness in breast cancer cells.