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Rigidity sensing and adaptation through regulation of integrin types

Nature Materials volume 13, pages 631–637 (2014)Cite this article

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Abstract

Tissue rigidity regulates processes in development, cancer and wound healing. However, how cells detect rigidity, and thereby modulate their behaviour, remains unknown. Here, we show that sensing and adaptation to matrix rigidity in breast myoepithelial cells is determined by the bond dynamics of different integrin types. Cell binding to fibronectin through either α5β1 integrins (constitutively expressed) or αvβ6 integrins (selectively expressed in cancer and development) adapts force generation, actin flow and integrin recruitment to rigidities associated with healthy or malignant tissue, respectively. In vitro experiments and theoretical modelling further demonstrate that this behaviour is explained by the different binding and unbinding rates of both integrin types to fibronectin. Moreover, rigidity sensing through differences in integrin bond dynamics applies both when integrins bind separately and when they compete for binding to fibronectin.

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Figure 1: Expression of αvβ6 integrins alters response to substrate stiffness.
Figure 2: Both binding and unbinding rates to FN are higher for αvβ6 than for α5β1.
Figure 3: Integrin–FN clutch model of force transmission.
Figure 4: Integrin–FN binding dynamics predict force generation, actin flow and integrin recruitment in response to substrate stiffness.

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Acknowledgements

We acknowledge support from the Spanish Ministry for Economy and Competitiveness (BFU2011-23111 and BFU2012-38146), a Career Integration Grant within the seventh European Community Framework Programme (PCIG10-GA-2011-303848), the European Research Council (Grant Agreement 242993), the Generalitat de Catalunya, Fundació La Caixa, Fundació la Marató de TV3 (project 20133330), and the Breast Cancer Campaign Tissue Bank. We thank P. Rodríguez, M. Taulés, L. Bardia, M. Rodríguez, V. González, V. Conte, A. Brugués, D. Zalvidea, D. Navajas, A. del Rio and the members of the X.T. and P.R-C. laboratories for technical assistance and discussions.

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Authors and Affiliations

  1. Centre for Tumour Biology Barts Cancer Institute—a Cancer Research UK Centre of Excellence, Queen Mary, University of London, London EC1M 6BQ, UK

    Alberto Elosegui-Artola, Michael D. Allen, Jennifer J. Gomm, John F. Marshall & J. Louise Jones

  2. Institute for Bioengineering of Catalonia, 08028 Barcelona, Spain

    Alberto Elosegui-Artola, Elsa Bazellières, Roger Oria, Raimon Sunyer, Xavier Trepat & Pere Roca-Cusachs

  3. CEIT and TECNUN (University of Navarra), 20018 Donostia-San Sebastian, Spain

    Ion Andreu

  4. University of Barcelona, 08028 Barcelona, Spain

    Xavier Trepat & Pere Roca-Cusachs

  5. Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain

    Xavier Trepat

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  1. Alberto Elosegui-Artola
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Contributions

A.E-A., M.D.A., J.F.M., J.L.J., X.T. and P.R-C. designed research, A.E-A., E.B., I.A., R.O. and R.S. performed experiments, M.D.A., R.S., J.J.G. and P.R-C. contributed new reagents/analytical tools, A.E-A., E.B., M.D.A., J.F.M., J.L.J., X.T. and P.R-C. analysed the data, P.R-C. implemented the computational model, and A.E-A., X.T. and P.R-C. wrote the paper. All authors read the manuscript and commented on it.

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Correspondence to Xavier Trepat or Pere Roca-Cusachs.

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Elosegui-Artola, A., Bazellières, E., Allen, M. et al. Rigidity sensing and adaptation through regulation of integrin types. Nature Mater 13, 631–637 (2014). https://doi.org/10.1038/nmat3960

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