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Directed migration of cancer cells guided by the graded texture of the underlying matrix

Nature Materials volume 15, pages 792–801 (2016)Cite this article

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Abstract

Living cells and the extracellular matrix (ECM) can exhibit complex interactions that define key developmental, physiological and pathological processes. Here, we report a new type of directed migration—which we term ‘topotaxis’—guided by the gradient of the nanoscale topographic features in the cells’ ECM environment. We show that the direction of topotaxis is reflective of the effective cell stiffness, and that it depends on the balance of the ECM-triggered signalling pathways PI(3)K–Akt and ROCK–MLCK. In melanoma cancer cells, this balance can be altered by different ECM inputs, pharmacological perturbations or genetic alterations, particularly a loss of PTEN in aggressive melanoma cells. We conclude that topotaxis is a product of the material properties of cells and the surrounding ECM, and propose that the invasive capacity of many cancers may depend broadly on topotactic responses, providing a potentially attractive mechanism for controlling invasive and metastatic behaviour.

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Figure 1: Topotactic migration of melanoma cells guided by the gradient of the post density and pre-coated ECM density.
Figure 2: Correlation of the topotactic migration direction and cell stiffness as a function of the local post density.
Figure 3: Modulation of topotaxis direction of 1205Lu cells by perturbations of PI(3)K and ROCK signalling.
Figure 4: Functional PTEN in non-invasive SBcl2 modulates its topotactic properties accounting for the responses shown in Fig. 1.
Figure 5: Modulation of topotaxis direction of SBcl2 cells by perturbations of PI(3)K and ROCK signalling.
Figure 6: A schematic graphic model of the topotaxis in invasive and non-invasive cells.

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  • 22 March 2016

    In the version of the Article originally published, the original title omitted a word and should have read 'Directed migration of cancer cells guided by the graded texture of the underlying matrix'. This has been corrected in all versions of the Article.

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Acknowledgements

We thank R. Alani (Boston University) for sharing melanoma cell lines and J. Zhang for sharing plasmids (UCSD); and A. Pellowe and A. L. Gonzalez (Yale University) for help with SEM imaging. J.P. is a recipient of a Samsung scholarship. This work was also supported by NIH grants U01CA15578 and CA16359 (Yale Cancer Center) to A.L. and HL107361, U54 CA141868 and P50 CA103175 to S.S.A. D.-H.K. thanks the Department of Bioengineering at the University of Washington for the new faculty startup fund.

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Authors and Affiliations

  1. Department of Biomedical Engineering, Yale University, New Haven, Connecticut 06520, USA

    JinSeok Park & Andre Levchenko

  2. Yale Systems Biology Institute, Yale University, West Haven, Connecticut 06516, USA

    JinSeok Park & Andre Levchenko

  3. Departments of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

    JinSeok Park, Chiaochun Joanne Wang & Eunmi Hur

  4. Department of Bioengineering, University of Washington, Seattle, Washington 98195, USA

    Deok-Ho Kim

  5. Department of Mechanical and Aerospace Engineering, Seoul National University, Seoul 151-742, Republic of Korea

    Hong-Nam Kim, Moon Kyu Kwak & Kahp-Yang Suh

  6. Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA

    Steven S. An

  7. Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland 21218, USA

    Steven S. An

  8. Physical Sciences-Oncology Center, Johns Hopkins University, Baltimore, Maryland 21218, USA

    Steven S. An

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Contributions

J.P., D.-H.K. and A.L. conceived and designed the project. J.P. performed the experiments. D.-H.K., H.-N.K. and M.K.K. designed and fabricated substrata under the supervision of A.L. and K.-Y.S. J.P. and E.H. tracked and analysed migration time-lapse data. C.J.W. transfected plasmids and made cell lines. A.L. and S.S.A. supervised the project. J.P. and A.L. wrote the manuscript. A.L. and S.S.A. reviewed and revised the manuscript.

Corresponding authors

Correspondence to Steven S. An or Andre Levchenko.

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Competing interests

C.J.W.’s contribution to this work occurred while she was employed by the Johns Hopkins University and does not reflect the views or policies of her current employer, the US Food and Drug Administration.

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Park, J., Kim, DH., Kim, HN. et al. Directed migration of cancer cells guided by the graded texture of the underlying matrix. Nature Mater 15, 792–801 (2016). https://doi.org/10.1038/nmat4586

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