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Collective cell migration requires suppression of actomyosin at cell–cell contacts mediated by DDR1 and the cell polarity regulators Par3 and Par6

Nature Cell Biology volume 13, pages 49–59 (2011)Cite this article

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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.

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Figure 1: DDR1 is required for collective cell migration.
Figure 2: DDR1 does not require kinase activity or collagen binding to regulate actomyosin at cell contacts.
Figure 3: DDR1 interacts with Par3 and Par 6.
Figure 4: Par3 and Par6 are required for efficient collective invasion.
Figure 5: DDR1 controls RhoE localization at cell–cell contacts.
Figure 6: Actomyosin organization in collective cell migration.

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Acknowledgements

We thank Cancer Research UK and EMBO for funding and B. Thompson, N. Tapon and lab members for comments and discussion. We also thank the Experimental Pathology lab for technical help.

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Authors and Affiliations

  1. Tumour Cell Biology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, WC2A 3PX, London, UK

    Cristina Hidalgo-Carcedo, Steven Hooper, Shahid I. Chaudhry & Erik Sahai

  2. St George's Hospital, Tooting, SW17 0QT, London, UK

    Peter Williamson

  3. Institute of Cancer Research, 237 Fulham Road, SW3 6JB, London, UK

    Kevin Harrington

  4. National Heart and Lung Institute, Imperial College London, South Kensington Campus, SW7 2AZ, London, UK

    Birgit Leitinger

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Contributions

C.H.C. and E.S. conceived and designed the experiments. C.H.C. performed all experiments except Figs 1a, e and 5c, d, f. Supplementary Information, Figures S1, S2 and S5c were performed by E.S. Fig 4b and various molecular cloning procedures were performed by S.H. The clinical samples used in Supplementary Information, Figures S1 and S6 were collected by S.I.C., P.W. and K.H.

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Correspondence to Erik Sahai.

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Hidalgo-Carcedo, C., Hooper, S., Chaudhry, S. et al. Collective cell migration requires suppression of actomyosin at cell–cell contacts mediated by DDR1 and the cell polarity regulators Par3 and Par6. Nat Cell Biol 13, 49–59 (2011). https://doi.org/10.1038/ncb2133

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