Epithelia act as a barrier against environmental stress and abrasion and in vivo they are continuously exposed to environments of various mechanical properties. The impact of this environment on epithelial integrity remains elusive. By culturing epithelial cells on 2D hydrogels, we observe a loss of epithelial monolayer integrity through spontaneous hole formation when grown on soft substrates. Substrate stiffness triggers an unanticipated mechanical switch of epithelial monolayers from tensile on soft to compressive on stiff substrates. Through active nematic modelling, we find that spontaneous half-integer defect formation underpinning large isotropic stress fluctuations initiate hole opening events. Our data show that monolayer rupture due to high tensile stress is promoted by the weakening of cell-cell junctions that could be induced by cell division events or local cellular stretching. Our results show that substrate stiffness provides feedback on monolayer mechanical state and that topological defects can trigger stochastic mechanical failure, with potential application towards a mechanistic understanding of compromised epithelial integrity during immune response and morphogenesis.

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.

Many types of motile cells perform durotaxis, namely directed migration following gradients of substrate stiffness. Recent experiments have revealed that cell monolayers can migrate toward stiffer regions even when individual cells do not—a phenomenon known as collective durotaxis. Here, we address the spontaneous motion of finite cohesive cell monolayers on a stiffness gradient. We theoretically analyze a continuum active polar fluid model that has been tested in recent wetting assays of epithelial tissues and includes two types of active forces (cell–substrate traction and cell–cell contractility). The competition between the two active forces determines whether a cell monolayer spreads or contracts. Here, we show that this model generically predicts collective durotaxis, and that it features a variety of dynamical regimes as a result of the interplay between the spreading state and the global propagation, including sequential contraction and spreading of the monolayer as it moves toward higher stiffness. We solve the model exactly in some relevant cases, which provides both physical insights into the mechanisms of tissue durotaxis and spreading as well as a variety of predictions that could guide the design of future experiments. Graphic 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.