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Motility-limited aggregation of mammary epithelial cells into fractal-like clusters

Susan E. Leggett,Zachary J. Neronha,Dhananjay Bhaskar,J. Y. Sim,T. M. Perdikari,I. Wong

Published 2019 in Proceedings of the National Academy of Sciences of the United States of America

ABSTRACT

Significance Individually migrating cells cluster into multicellular tissues during tissue formation, inflammation, and cancer. The corresponding increase in cell density can result in arrested motion, analogous to the “jamming” of soft materials such as glasses and gels. Here, we show that cells with reduced motility and proliferation organize into branching clusters, reminiscent of aggregation in nonliving colloidal particles. Subsequently, “leader cells” guide collective migration to link clusters together into spanning networks. These arrested dynamics occur at unusually low density and are reminiscent of gelation. Furthermore, increased motility and proliferation recover a glass-like transition at higher density. Overall, arrested motion in living cells has striking similarities with nonliving colloidal particles, suggesting physical signatures of clustering and branching morphogenesis in development and disease. Migratory cells transition between dispersed individuals and multicellular collectives during development, wound healing, and cancer. These transitions are associated with coordinated behaviors as well as arrested motility at high cell densities, but remain poorly understood at lower cell densities. Here, we show that dispersed mammary epithelial cells organize into arrested, fractal-like clusters at low density in reduced epidermal growth factor (EGF). These clusters exhibit a branched architecture with a fractal dimension of Df=1.7, reminiscent of diffusion-limited aggregation of nonliving colloidal particles. First, cells display diminished motility in reduced EGF, which permits irreversible adhesion upon cell–cell contact. Subsequently, leader cells emerge that guide collectively migrating strands and connect clusters into space-filling networks. Thus, this living system exhibits gelation-like arrest at low cell densities, analogous to the glass-like arrest of epithelial monolayers at high cell densities. We quantitatively capture these behaviors with a jamming-like phase diagram based on local cell density and EGF. These individual to collective transitions represent an intriguing link between living and nonliving systems, with potential relevance for epithelial morphogenesis into branched architectures.

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