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.

中文翻译：

---

Coronin 1C 通过调节 MT1-MMP 流量和侵袭伪足功能促进三阴性乳腺癌侵袭。

膜 1 型基质金属蛋白酶 (MT1-MMP) 是一种膜束缚蛋白酶，是癌症侵袭和转移过程中基质分解的关键。MT1-MMP 流量和基质降解侵袭伪足的形成需要 Arp2/3 复合体组装分支肌动蛋白网络。与肌动蛋白丝分支因子 cortactin 在癌细胞侵袭期间侵袭伪足功能中的公认作用形成对比，冠蛋白家族脱支因子对基于侵袭伪足的基质重塑的贡献尚不清楚。在这里，我们调查了 coronin 1C 对乳腺癌细胞侵袭潜能的贡献。我们报道了侵袭性人类乳腺癌中 coronin 1C 的表达升高，与转移风险增加相关的 MT1-MMP 表达呈正相关，并且是乳腺癌中新的独立预后因素。我们提供的证据表明，类似于 cortactin，coronin 1C 是乳腺癌细胞系的侵袭伪足形成和基质降解以及多细胞球体的 3D 胶原蛋白入侵所必需的。使用原位人乳腺肿瘤异种移植物的活体成像，我们发现 coronin 1C 在与肿瘤微环境中的胶原纤维相关联的结构中积累。此外，我们确定了 coronin 1C 在调节 MT1-MMP 阳性内溶酶体的定位和运输中的作用。这些结果将 coronin 1C 确定为负责侵袭伪足形成的多方面机制的新参与者，