25 August 2020

In Nature Cell Biology (NCB), Peter Friedl, Olga Ilina, Pavlo Grytsenko, Gert-Jan Bakker and Manon Vullings, theme Cancer development & immune defence, Peter Bult, theme Women's cancers, describe that during tumor development the way cells move can change from coordinated, collective behavior to individual, chaotic behavior. This insight could improve the diagnosis and therapy of cancer in the future.

Plasticity of cancer invasion and metastasis depends on the ability of cancer cells to switch between collective and single-cell dissemination, controlled by cadherin-mediated cell–cell junctions. In clinical samples, E-cadherin-expressing and -deficient tumours both invade collectively and metastasize equally, implicating additional mechanisms controlling cell–cell cooperation and individualization. Here, using spatially defined organotypic culture, intravital microscopy of mammary tumours in mice and in silico modelling, we identify cell density regulation by three-dimensional tissue boundaries to physically control collective movement irrespective of the composition and stability of cell–cell junctions. Deregulation of adherens junctions by downregulation of E-cadherin and p120-catenin resulted in a transition from coordinated to uncoordinated collective movement along extracellular boundaries, whereas single-cell escape depended on locally free tissue space. These results indicate that cadherins and extracellular matrix confinement cooperate to determine unjamming transitions and stepwise epithelial fluidization towards, ultimately, cell individualization.

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