Identification of CD44 as a key engager to hyaluronic acid-rich extracellular matrices for cell traction force generation and tumor invasion in 3D.

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 integrin cell surface adhesion receptors. 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.