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Collective and individual migration following the epithelial–mesenchymal transition

Nature Materials volume 13, pages 1063–1071 (2014)Cite this article

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Abstract

During cancer progression, malignant cells in the tumour invade surrounding tissues. This transformation of adherent cells to a motile phenotype has been associated with the epithelial–mesenchymal transition (EMT). Here, we show that EMT-activated cells migrate through micropillar arrays as a collectively advancing front that scatters individual cells. Individual cells with few neighbours dispersed with fast, straight trajectories, whereas cells that encountered many neighbours migrated collectively with epithelial biomarkers. We modelled these emergent dynamics using a physical analogy to phase transitions during binary-mixture solidification, and validated it using drug perturbations, which revealed that individually migrating cells exhibit diminished chemosensitivity. Our measurements also indicate a degree of phenotypic plasticity as cells interconvert between individual and collective migration. The study of multicellular behaviours with single-cell resolution should enable further quantitative insights into heterogeneous tumour invasion.

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Figure 1: Epithelial and mesenchymal cells migrate collectively and individually within enclosed micropillar arrays.
Figure 2: Differences in migratory behaviour associated with collective or individual migration phenotypes were classified using a Gaussian mixture model.
Figure 3: The dynamics of individual scattering from a collectively migrating front can be understood as a dispersion phenomenon from a moving interface.
Figure 4: Perturbation of invasion behaviours in different cell lines with different Rsk pathway inhibitors.

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References

  1. Fidler, I. J. & Hart, I. R. Biological diversity in metastatic neoplasms: Origins and implications. Science 217, 998–1003 (1982).

    Article  CAS  Google Scholar 

  2. Willis, R. A. The Spread of Tumours in The Human Body 3rd edn (Butterworths, 1973).

    Google Scholar 

  3. Thiery, J. P., Acloque, H., Huang, R. Y. J. & Nieto, M. A. Epithelial–mesenchymal transitions in development and disease. Cell 139, 871–890 (2009).

    Article  CAS  Google Scholar 

  4. Polyak, K. & Weinberg, R. A. Transitions between epithelial and mesenchymal states: Acquisition of malignant and stem cell traits. Nature Rev. Cancer 9, 265–273 (2009).

    Article  CAS  Google Scholar 

  5. Yilmaz, M. & Christofori, G. EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev. 28, 15–33 (2009).

    Article  Google Scholar 

  6. Singh, A. & Settleman, J. EMT, cancer stem cells and drug resistance: An emerging axis of evil in the war on cancer. Oncogene 29, 4741–4751 (2010).

    Article  CAS  Google Scholar 

  7. Friedl, P., Locker, J., Sahai, E. & Segall, J. E. Classifying collective cancer cell invasion. Nature Cell Biol. 14, 777–783 (2012).

    Article  Google Scholar 

  8. Polacheck, W. J., Zervantonakis, I. K. & Kamm, R. D. Tumor cell migration in complex microenvironments. Cell. Mol. Life Sci. 70, 1335–1356 (2013).

    Article  CAS  Google Scholar 

  9. Thompson, E. W., Newgreen, D. F. & Tarin, D. Carcinoma invasion and metastasis: A role for epithelial–mesenchymal transition? Cancer Res. 65, 5991–5995 (2005).

    Article  CAS  Google Scholar 

  10. Wang, W. et al. Single cell behavior in metastatic primary mammary tumors correlated with gene expression patterns revealed by molecular profiling. Cancer Res. 62, 6278–6288 (2002).

    CAS  Google Scholar 

  11. Alexander, S., Koehl, G. E., Hirschberg, M., Geissler, E. K. & Friedl, P. Dynamic imaging of cancer growth and invasion: A modified skin-fold chamber model. Histochem. Cell Biol. 130, 1147–1154 (2008).

    Article  CAS  Google Scholar 

  12. Giampieri, S. et al. Localized and reversible TGFβ signalling switches breast cancer cells from cohesive to single cell motility. Nature Cell Biol. 11, 1287–1296 (2009).

    Article  CAS  Google Scholar 

  13. Simpson, K. J. et al. Identification of genes that regulate epithelial cell migration using an siRNA screening approach. Nature Cell Biol. 10, 1027–1038 (2008).

    Article  CAS  Google Scholar 

  14. Vitorino, P. & Meyer, T. Modular control of endothelial sheet migration. Genes Dev. 22, 3268–3281 (2008).

    Article  CAS  Google Scholar 

  15. Boyden, S. The chemotactic effect of mixtures of antibody and antigen on polymorphonuclear leucocytes. J. Exp. Med. 115, 453–466 (1962).

    Article  CAS  Google Scholar 

  16. Farooqui, R. & Fenteany, G. Multiple rows of cells behind an epithelial wound edge extend cryptic lamellipodia to collectively drive cell-sheet movement. J. Cell Sci. 118, 51–63 (2005).

    Article  CAS  Google Scholar 

  17. Poujade, M. et al. Collective migration of an epithelial monolayer in response to a model wound. Proc. Natl Acad. Sci. USA 104, 15988–15993 (2007).

    Article  CAS  Google Scholar 

  18. Ng, M. R., Besser, A., Danuser, G. & Brugge, J. S. Substrate stiffness regulates cadherin-dependent collective migration through myosin-II contractility. J. Cell Biol. 199, 545–563 (2012).

    Article  CAS  Google Scholar 

  19. Tambe, D. T. et al. Collective cell guidance by cooperative intercellular forces. Nature Mater. 10, 469–475 (2011).

    Article  CAS  Google Scholar 

  20. Bindschadler, M. & McGrath, J. L. Sheet migration by wounded monolayers as an emergent property of single-cell dynamics. J. Cell Sci. 120, 876–884 (2007).

    Article  CAS  Google Scholar 

  21. Nnetu, K. D., Knorr, M., Strehle, D., Zink, M. & Käs, J. A. Directed persistent motion maintains sheet integrity during multi-cellular spreading and migration. Soft Matter 8, 6913–6921 (2012).

    Article  CAS  Google Scholar 

  22. Irimia, D. Microfluidic technologies for temporal perturbations of chemotaxis. Annu. Rev. Biomed. Eng. 12, 259–284 (2010).

    Article  CAS  Google Scholar 

  23. Pathak, A. & Kumar, S. Biophysical regulation of tumor cell invasion: Moving beyond matrix stiffness. Integr. Biol. 3, 267–278 (2011).

    Article  CAS  Google Scholar 

  24. Cano, A. et al. The transcription factor Snail controls epithelial–mesenchymal transitions by repressing E-cadherin expression. Nature Cell Biol. 2, 76–83 (2000).

    Article  CAS  Google Scholar 

  25. Zhou, B. P. et al. Dual regulation of Snail by GSK-3β-mediated phosphorylation in control of epithelial–mesenchymal transition. Nature Cell Biol. 6, 931–940 (2004).

    Article  CAS  Google Scholar 

  26. Javaid, S. et al. Dynamic chromatin modification sustains epithelial–mesenchymal transition following inducible expression of Snail-1. Cell Rep. 5, 1679–1689 (2013).

    Article  CAS  Google Scholar 

  27. Overholtzer, M. et al. Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon. Proc. Natl Acad. Sci. USA 103, 12405–12410 (2006).

    Article  CAS  Google Scholar 

  28. Altschuler, S. J. & Wu, L. F. Cellular heterogeneity: Do differences make a difference? Cell 141, 559–563 (2010).

    Article  CAS  Google Scholar 

  29. Irimia, D. & Toner, M. Spontaneous migration of cancer cells under conditions of mechanical confinement. Integr. Biol. 1, 506–512 (2009).

    Article  CAS  Google Scholar 

  30. Jaqaman, K. et al. Robust single-particle tracking in live-cell time-lapse sequences. Nature Methods 5, 695–702 (2008).

    Article  CAS  Google Scholar 

  31. Hung, W. C. et al. Distinct signaling mechanisms regulate migration in unconfined versus confined spaces. J. Cell Biol. 202, 807–824 (2013).

    Article  CAS  Google Scholar 

  32. Pathak, A. & Kumar, S. Independent regulation of tumor cell migration by matrix stiffness and confinement. Proc. Natl Acad. Sci. USA 109, 10334–10339 (2012).

    Article  CAS  Google Scholar 

  33. Wolf, K. et al. Physical limits of cell migration: Control by ECM space and nuclear deformation and tuning by proteolysis and traction force. J. Cell Biol. 201, 1069–1084 (2013).

    Article  CAS  Google Scholar 

  34. Worster, M. G. Solidification of an alloy from a cooled boundary. J. Fluid Mech. 167, 481–501 (1986).

    Article  CAS  Google Scholar 

  35. Smolen, G. A. et al. A genome-wide RNAi screen identifies multiple RSK-dependent regulators of cell migration. Genes Dev. 24, 2654–2665 (2010).

    Article  CAS  Google Scholar 

  36. Cohen, M. S., Zhang, C., Shokat, K. M. & Taunton, J. Structural bioinformatics-based design of selective, irreversible kinase inhibitors. Science 308, 1318–1321 (2005).

    Article  CAS  Google Scholar 

  37. Brabletz, T. To differentiate or not–routes towards metastasis. Nature Rev. Cancer 12, 425–436 (2012).

    Article  CAS  Google Scholar 

  38. Balzer, E. M. et al. Physical confinement alters tumor cell adhesion and migration phenotypes. FASEB J. 26, 4045–4056 (2012).

    Article  CAS  Google Scholar 

  39. Steinberg, M. S. Differential adhesion in morphogenesis: A modern view. Curr. Opin. Genet. Dev. 17, 281–286 (2007).

    Article  CAS  Google Scholar 

  40. Worster, M. G. Convection in mushy layers. Annu. Rev. Fluid Mech. 29, 91–122 (1997).

    Article  Google Scholar 

  41. Guiot, C., Pugno, N., Delsanto, P. P. & Deisboeck, T. S. Physical aspects of cancer invasion. Phys. Biol. 4, 1–6 (2007).

    Article  Google Scholar 

  42. Anjum, R. & Blenis, J. The RSK family of kinases: Emerging roles in cellular signalling. Nature Rev. Mol. Cell Biol. 9, 747–758 (2008).

    Article  CAS  Google Scholar 

  43. de Rooij, J., Kerstens, A., Danuser, G., Schwartz, M. A. & Waterman-Storer, C. M. Integrin-dependent actomyosin contraction regulates epithelial cell scattering. J. Cell Biol. 171, 153–164 (2005).

    Article  CAS  Google Scholar 

  44. Mark, S. et al. Physical model of the dynamic instability in an expanding cell culture. Biophys. J. 98, 361–370 (2010).

    Article  CAS  Google Scholar 

  45. Rolli, C. G. et al. Switchable adhesive substrates: Revealing geometry dependence in collective cell behavior. Biomaterials 33, 2409–2418 (2012).

    Article  CAS  Google Scholar 

  46. Nunes, J. K., Tsai, S. S. H., Wan, J. & Stone, H. A. Dripping and jetting in microfluidic multiphase flows applied to particle and fiber synthesis. J. Phys. D 46, 114002 (2013).

    Article  Google Scholar 

  47. Rolli, C. G., Seufferlein, T., Kemkemer, R. & Spatz, J. P. Impact of tumor cell cytoskeleton organization on invasiveness and migration: A microchannel-based approach. PLoS ONE 5, e8726 (2010).

    Article  Google Scholar 

  48. Sharma, S. V., Haber, D. A. & Settleman, J. Cell line-based platforms to evaluate the therapeutic efficacy of candidate anticancer agents. Nature Rev. Cancer 10, 241–253 (2010).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank J. Taunton for the gift of FMK-MEA, A. Besser and G. Danuser for assistance with cell tracking, and O. Hurtado for assistance with fabrication. This work was supported by the Merck Fellowship of the Damon Runyon Cancer Research Foundation (DRG-2065-10) to I.Y.W., the Howard Hughes Medical Institute to D.A.H., as well as the National Institutes of Health under CA129933 to D.A.H., EB002503 (BioMEMS Resource Center) to M.T., and CA135601 and GM092804 to D.I.

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  1. Ian Y. Wong

    Present address: Present address: Center for Biomedical Engineering, School of Engineering. Brown University, Providence, Rhode Island 02912, USA.,

Authors and Affiliations

  1. Department of Surgery, BioMEMS Resource Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA

    Ian Y. Wong, Elisabeth A. Wong, Sinem Perk, Mehmet Toner & Daniel Irimia

  2. Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA

    Sarah Javaid & Daniel A. Haber

  3. Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA

    Daniel A. Haber

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Contributions

D.A.H. and D.I. conceived the project; I.Y.W., S.J., D.A.H., M.T. and D.I. designed the research; I.Y.W., S.J. and E.A.W. performed the experiments; I.Y.W. and E.A.W. performed image analysis; I.Y.W., E.A.W. and S.P. performed data analysis; I.Y.W. and M.T. developed the theoretical model; I.Y.W., M.T. and D.I. wrote the manuscript with feedback from S.J., E.A.W., S.P. and D.A.H. All authors reviewed the data and final manuscript.

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Correspondence to Daniel Irimia.

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Wong, I., Javaid, S., Wong, E. et al. Collective and individual migration following the epithelial–mesenchymal transition. Nature Mater 13, 1063–1071 (2014). https://doi.org/10.1038/nmat4062

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