Stiffness-dependent active wetting enables optimal collective cell durotaxis

Abstract

The directed migration of cellular clusters enables morphogenesis, wound healing, and collective cancer invasion. Gradients of substrate stiffness are known to direct the migration of cellular clusters in a process called collective durotaxis, but underlying mechanisms remain unclear. Here, we unveil a connection between collective durotaxis and the wetting properties of cellular clusters. We show that clusters of cancer cells dewet soft substrates and wet stiff ones. At intermediate stiffness, at the crossover from low to high wettability, clusters on uniform-stiffness substrates become maximally motile, and clusters on stiffness gradients exhibit optimal durotaxis. Durotactic velocity increases with cluster size, stiffness gradient, and actomyosin activity. We demonstrate this behavior on substrates coated with the cell-cell adhesion protein E-cadherin and then establish its generality on substrates coated with extracellular matrix. We develop a physical model of three-dimensional active wetting that explains this mode of collective durotaxis in terms of a balance between in-plane active traction and tissue contractility, and out-of-plane surface tension. Finally, we show that the distribution of cluster displacements has a heavy tail, with infrequent but large cellular hops that contribute to durotactic migration. Our study demonstrates a physical mechanism of collective durotaxis, through both cell-cell and cell-substrate adhesion ligands, based on the wetting properties of active droplets.

Amoeboid cells undergo durotaxis with soft end polarized NMIIA

“…Aside from NMIIA, other mechanisms may also facilitate amoeboid durotaxis. Inorganic droplets can move directionally on surfaces with stiffness gradient due to the intrinsic wettability (52,53).…”

“…The well-established motor-clutch model (58) and random walk model (59) demonstrate that cell durotaxis is attributable to traction or cell-substrate adhesion difference. Vertex model (60) and continuum model (53) are widely used in collective durotaxis, focusing on long-range environmental stiffness difference and force generation between adjacent cells and suggesting far more efficiency in collective durotaxis than single-cell durotaxis. The active nematic model employs active extensile or contractile agents to push or pull the fluid along their elongation axis to simulate cell flowing (61).…”