Roughness and dynamics of proliferating cell fronts as a probe of cell-cell interactions

Abstract

Juxtacellular interactions play an essential but still not fully understood role in both normal tissue development and tumour invasion. Using proliferating cell fronts as a model system, we explore the effects of cell-cell interactions on the geometry and dynamics of these one-dimensional biological interfaces. We observe two distinct scaling regimes of the steady state roughness of in-vitro propagating Rat1 fibroblast cell fronts, suggesting different hierarchies of interactions at sub-cell lengthscales and at a lengthscale of 2-10 cells. Pharmacological modulation significantly affects the proliferation speed of the cell fronts, and those modulators that promote cell mobility or division also lead to the most rapid evolution of cell front roughness. By comparing our experimental observations to numerical simulations of elastic cell fronts with purely short-range interactions, we demonstrate that the interactions at few-cell lengthscales play a key role. Our methodology provides a simple framework to measure and characterise the biological effects of such interactions, and could be useful in tumour phenotyping. Proliferating cell fronts underpin wound healing, tumour invasion, and morphogenesis, and are governed by a complex and still not fully understood interplay of multiple mechanical and chemical factors. From a physics perspective, these cell fronts can be described as elastic interfaces in disordered media. Thus, analysing their geometric properties and dynamics can reveal the characteristic lengthscales of the dominant interactions, and point towards the underlying biological pathways. Here, we show that the roughness of proliferating fronts of Rat1 fibroblasts is governed by two different hierarchies of interactions, with distinct behaviour at sub-cell and few-cell lengthscales. Using in-vitro scratch assays, we find moreover that pharmacological modulators significantly affect the proliferation speed of the cell fronts as well as the evolution of their roughness, increased when cell-cell communication via gap junctions is perturbed, and decreased when cell division is repressed. We determine that our experimental observations cannot be reproduced by numerical simulations of elastic cell fronts with purely short-range interactions, demonstrating the key role of juxtacellular interactions at few-cell lengthscales. Our approach provides a simple framework to measure and characterise the biological effects of such interactions, and could be useful in tumour phenotyping.