Directional collective cell migration (DCCM) is crucial for morphogenesis and cancer metastasis. P-cadherin (also known as CDH3), which is a cell-cell adhesion protein expressed in carcinoma and aggressive sarcoma cells and associated with poor prognosis, is a major DCCM regulator. However, it is unclear how P-cadherin-mediated mechanical coupling between migrating cells influences force transmission to the extracellular matrix (ECM). Here, we found that decorin, a small proteoglycan that binds to and organizes collagen fibers, is specifically expressed and secreted upon P-cadherin, but not E- and R-cadherin (also known as CDH1 and CDH4, respectively) expression. Through cell biological and biophysical approaches, we demonstrated that decorin is required for P-cadherin-mediated DCCM and collagen fiber orientation in the migration direction in 2D and 3D matrices. Moreover, P-cadherin, through decorin-mediated collagen fiber reorientation, promotes the activation of β1 integrin and of the β-Pix (ARHGEF7)/CDC42 axis, which increases traction forces, allowing DCCM. Our results identify a novel P-cadherin-mediated mechanism to promote DCCM through ECM remodeling and ECM-guided cell migration.

中文翻译：

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P-钙黏着蛋白诱导的核心蛋白聚糖分泌是胶原纤维排列和定向集体细胞迁移所必需的。

定向集体细胞迁移（DCCM）对于形态发生和癌症转移至关重要。P-cadherin（也称为CDH3）是一种主要的DCCM调节剂，它是一种在癌细胞和侵袭性肉瘤细胞中表达的细胞粘附蛋白，与预后不良有关。但是，尚不清楚迁移细胞之间P-钙粘蛋白介导的机械偶联如何影响向细胞外基质（ECM）的力传递。在这里，我们发现了除蛋白，一种与蛋白纤维结合并组织胶原蛋白的小蛋白聚糖，在P-cadherin上特异性表达和分泌，而在E-和R-cadherin（分别称为CDH1和CDH4）表达上却没有表达。通过细胞生物学和生物物理方法，我们证明了在2D和3D矩阵中，P-钙黏着蛋白介导的DCCM和胶原纤维在迁移方向上的取向需要decorin。此外，P-钙粘着蛋白通过核心蛋白聚糖介导的胶原纤维重新定向，促进β1整联蛋白和β-Pix（ARHGEF7）/ CDC42轴的活化，从而增加了牵引力，从而实现了DCCM。我们的结果确定了一种新的P-钙粘蛋白介导的机制，可通过ECM重塑和ECM指导的细胞迁移来促进DCCM。