How forces modulate cellular dynamics: from the immune response to gene expression
Cells need to sense and adaptively respond to their physical environment in diverse biological contexts such as development, cancer and the immune response. In addition to chemical signals and the genetic blueprint, cellular function and dynamics are modulated by the physical properties of their environment such as stiffness and topography. In order to probe and respond to these environmental attributes, cells exert forces on their surroundings and generate appropriate biochemical and genetic responses. These forces arise from the spatiotemporalorganization and dynamics of the cell cytoskeleton, a network of entangled biopolymer filaments that is driven out of thermal equilibrium by enzymes that actively convert chemical energy to mechanical energy. Understanding how cells generate forces and sense the mechanical environment (mechanosensing) is an important challenge with implications for physics and biology. We have investigated the principles of cellular force generation, the statistical properties of these forces, and their role in stiffness and topography sensing by immune and cancer cells. We found that transmission of mechanical information from the external environment to biochemical networks inside the cell occurs by adaptive changes in the stability and mechanics of cytoskeletal networks. Using novel imaging methods and physical models, we have revealed that substrate stiffness regulates gene expression by controlling the binding of proteins to DNA. These results have implications for understanding how forces and material properties of the environment are actively transmitted to the nucleus to control cell fate and how mechanosensing is impaired in diseases such as cancer. Our work provides insight into the design principles underlying how biologically active matter controls signaling and gene expression and underscores the importance of physical forces in cellular function.