Mechanistic and experimental models of cell migration reveal the importance of intercellular interactions in cell invasion

Abstract

Moving fronts of cells are essential for development, repair and disease progression. Therefore, understanding and quantifying the details of the mechanisms that drive the movement of cell fronts is of wide interest. Quantitatively identifying the role of intercellular interactions, and in particular the role of cell pushing, remains an open question. Indeed, perhaps the most common continuum mathematical idealization of moving cell fronts is to treat the population of cells, either implicitly or explicitly, as a population of point particles undergoing a random walk that neglects intercellular interactions. In this work, we report a combined experimental-modelling approach showing that intercellular interactions contribute significantly to the spatial spreading of a population of cells. We use a novel experimental data set with PC-3 prostate cancer cells that have been pretreated with Mitomycin-C to suppress proliferation. This allows us to experimentally separate the effects of cell migration from cell proliferation, thereby enabling us to focus on the migration process in detail as the population of cells recolonizes an initially-vacant region in a series of two-dimensional experiments. We quantitatively model the experiments using a stochastic modelling framework, based on Langevin dynamics, which explicitly incorporates random motility and various intercellular forces including: (i) long range attraction (adhesion); and (ii) finite size effects that drive short range repulsion (pushing). Quantitatively comparing the ability of this model to describe the experimentally observed population-level behaviour provides us with quantitative insight into the roles of random motility and intercellular interactions. To quantify the mechanisms at play, we calibrate the stochastic model to match experimental cell density profiles to obtain estimates of cell diffusivity, D, and the amplitude of intercellular forces, f0. Our analysis shows that taking a standard modelling approach which ignores intercellular forces provides a poor match to the experimental data whereas incorporating intercellular forces, including short-range pushing and longer range attraction, leads to a faithful representation of the experimental observations. These results demonstrate a significant role for intercellular interactions in cell invasion.\n\nAuthor summaryMoving cell fronts are routinely observed in various physiological processes, such as wound healing, malignant invasion and embryonic morphogenesis. We explore the effects of a previously overlooked mechanism that contributes to population-level front movement: pushing. Our framework is flexible and incorporates range of reasonable biological phenomena, such as random motility, cell-to-cell adhesion, and pushing. We find that neglecting finite size effects and intercellular forces, such as cell pushing, reduces our ability to mimic and predict our experimental observations.