Enhancement effects of extracellular fluid viscosity and matrix stiffness on cancer cell mechanosensing

Cancer cells are in vivo situated in a complex and heterogeneous tumor microenvironment (TME) that includes various biochemical and biophysical cues, such as the elasticity of extracellular matrix (ECMwo) and the viscosity of extracellular fluid (ECF). ECF viscosity in TME is much higher than in normal tissue, but it is unclear how this increased viscosity works simultaneously with other biophysical cues (e.g., ECM stiffness) to influence cancer cell behavior. We experimentally observed that ECF viscosity can significantly enhance cellular mechanosensing behaviors (e.g., cell spreading, cell adhesion, and YAP/TAZ nuclear translocation) only on a stiff substrate, representing a novel enhancement of cell behaviors by distinct mechanical signals. To explore the mechanical mechanisms behind such enhancement phenomenon, we developed a viscosity-based motor-clutch model, with which we found that cells sense and respond to ECF viscosity and ECM stiffness by regulating integrin-ECM bonds in cell adhesion dynamics. These findings help us understand how different mechanical signals in the complex tumor microenvironment collaborate to influence cancer cell behaviors during the development of cancers.[Figure not available: see fulltext.].