Mechanical properties of the extracellular matrix (ECM) critically regulate a number of important cell functions including growth, differentiation and migration. Type I collagen and glycosaminoglycans (GAGs) are two primary components of ECMs that contribute to mammalian tissue mechanics, with the collagen fiber network sustaining tension, and GAGs withstanding compression. The architecture and stiffness of the collagen network are known to be important for cell-ECM mechanical interactions via cell surface adhesion receptor integrin. In contrast, studies of GAGs in modulating cell-ECM interactions are limited. Here, we present experimental studies on the roles of hyaluronic acid (HA) in single tumor cell traction force generation using a recently developed 3D cell traction force microscopy method. Our work reveals that CD44, a cell surface receptor to HA, is engaged in cell traction force generation in conjunction with β1-integrin. We find that HA significantly modifies the architecture and mechanics of the collagen fiber network, decreasing tumor cells’ propensity to remodel the collagen network, attenuating traction force generation, transmission distance, and tumor invasion. Our findings point to a novel role for CD44 in traction force generation, which can be a potential therapeutic target for diseases involving HA rich ECMs such as breast cancer and glioblastoma.

中文翻译：

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鉴定 CD44 是富含透明质酸的细胞外基质的关键接合剂，用于 3D 细胞牵引力的产生和肿瘤侵袭


细胞外基质 （ECM） 的机械特性关键调节许多重要的细胞功能，包括生长、分化和迁移。I 型胶原蛋白和糖胺聚糖 （GAG） 是 ECM 的两个主要成分，有助于哺乳动物组织力学，胶原纤维网络保持张力，而 GAG 承受压缩。众所周知，胶原蛋白网络的结构和刚度通过细胞表面粘附受体整合素对细胞-ECM 机械相互作用很重要。相比之下，GAGs 在调节细胞-ECM 相互作用方面的研究是有限的。在这里，我们使用最近开发的 3D 细胞牵引力显微镜方法介绍了透明质酸 （HA） 在单个肿瘤细胞牵引力产生中的作用的实验研究。我们的工作揭示了 CD44 是 HA 的细胞表面受体，与 β1-整合素一起参与细胞牵引力的产生。我们发现 HA 显着改变了胶原纤维网络的结构和机制，降低了肿瘤细胞重塑胶原网络的倾向，减弱了牵引力的产生、传输距离和肿瘤侵袭。我们的研究结果表明 CD44 在牵引力产生中具有新作用，这可能是涉及富含 HA ECM 的疾病（如乳腺癌和胶质母细胞瘤）的潜在治疗靶点。