Abstract
Collective cell migration occurs in a range of contexts: cancer cells frequently invade in cohorts while retaining cell-cell junctions. Here we show that collective invasion by cancer cells depends on decreasing actomyosin contractility at sites of cell-cell contact. When actomyosin is not downregulated at cell-cell contacts, migrating cells lose cohesion. We provide a molecular mechanism for this downregulation. Depletion of discoidin domain receptor 1 (DDR1) blocks collective cancer-cell invasion in a range of two-dimensional, three-dimensional and 'organotypic' models. DDR1 coordinates the Par3/Par6 cell-polarity complex through its carboxy terminus, binding PDZ domains in Par3 and Par6. The DDR1-Par3/Par6 complex controls the localization of RhoE to cell-cell contacts, where it antagonizes ROCK-driven actomyosin contractility. Depletion of DDR1, Par3, Par6 or RhoE leads to increased actomyosin contactility at cell-cell contacts, a loss of cell-cell cohesion and defective collective cell invasion.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Actomyosin / metabolism*
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Amino Acid Sequence
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Blotting, Western
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Cell Adhesion
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Cell Communication
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cell Line
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Cell Line, Tumor
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Cell Movement*
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Cell Polarity
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Discoidin Domain Receptor 1
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Green Fluorescent Proteins / genetics
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Green Fluorescent Proteins / metabolism
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Humans
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Microscopy, Fluorescence
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Protein Binding
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RNA Interference
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / metabolism*
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Sequence Homology, Amino Acid
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Tight Junctions / metabolism
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rho GTP-Binding Proteins / genetics
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rho GTP-Binding Proteins / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Cell Cycle Proteins
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Membrane Proteins
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PARD3 protein, human
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PARD6A protein, human
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Green Fluorescent Proteins
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Actomyosin
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DDR1 protein, human
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Discoidin Domain Receptor 1
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Receptor Protein-Tyrosine Kinases
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RND3 protein, human
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rho GTP-Binding Proteins