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Intracellular Mechanics and Activity of Breast Cancer Cells Correlate with Metastatic Potential

Abstract

Mechanics of cancer cells are directly linked to their metastatic potential, or ability to produce a secondary tumor at a distant site. Metastatic cells survive in the circulatory system in a non-adherent state, and can squeeze through barriers in the body. Such considerable structural changes in cells rely on rapid remodeling of internal structure and mechanics. While external mechanical measurements have demonstrated enhanced pliability of cancer cells with increased metastatic potential, little is known about dynamics of their interior and we expect that to change significantly in metastatic cells. We perform a comparative study, using particle-tracking to evaluate the intracellular mechanics of living epithelial breast cells with varying invasiveness. Particles in all examined cell lines exhibit super-diffusion with a scaling exponent of 1.4 at short lag times, likely related to active transport by fluctuating microtubules and their associated molecular motors. Specifics of probe-particle transport differ between the cell types, depending on the cytoskeleton network-structure and interactions with it. Our study shows that the internal microenvironment of the highly metastatic cells evaluated here is more pliable and their cytoskeleton is less dense than the poorly metastatic and benign cells. We thus reveal intracellular structure and mechanics that can support the unique function and invasive capabilities of highly metastatic cells.

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References

  1. 1.

    Discher, D. E., Janmey, P., & Wang, Y. L. (2005). Tissue cells feel and respond to the stiffness of their substrate. Science, 310, 1139–1143.

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    An, S. S., Fabry, B., Trepat, X., Wang, N., & Fredberg, J. J. (2006). Do biophysical properties of the airway smooth muscle in culture predict airway hyperresponsiveness? American Journal of Respiratory Cell and Molecular Biology, 35, 55–64.

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Suresh, S., Spatz, J., Mills, J. P., Micoulet, A., Dao, M., Lim, C. T., et al. (2005). Connections between single-cell biomechanics and human disease states: gastrointestinal cancer and malaria. Acta Biomaterialia, 1, 15–30.

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Shaked, N. T., Satterwhite, L. L., Telen, M. J., Truskey, G. A., and Wax, A. (2011). Quantitative microscopy and nanoscopy of sickle red blood cells performed by wide field digital interferometry. Journal of Biomedical Optics 16.

  5. 5.

    Kumar, S., & Weaver, V. (2009). Mechanics, malignancy, and metastasis: The force journey of a tumor cell. Cancer and Metastasis Reviews, 28, 113–127.

    PubMed  Article  Google Scholar 

  6. 6.

    Suresh, S. (2007). Biomechanics and biophysics of cancer cells. Acta Biomaterialia, 3, 413–438.

    PubMed  Article  Google Scholar 

  7. 7.

    Paszek, M. J., Zahir, N., Johnson, K. R., Lakins, J. N., Rozenberg, G. I., Gefen, A., et al. (2005). Tensional homeostasis and the malignant phenotype. Cancer Cell, 8, 241–254.

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Janmey, P. A., & Miller, R. T. (2011). Mechanisms of mechanical signaling in development and disease. Journal of Cell Science, 124, 9–18.

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Wirtz, D., Konstantopoulos, K., & Searson, P. C. (2011). The physics of cancer: the role of physical interactions and mechanical forces in metastasis. Nature Reviews Cancer, 11, 512–522.

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Guck, J., Schinkinger, S., Lincoln, B., Wottawah, F., Ebert, S., Romeyke, M., et al. (2005). Optical deformability as an inherent cell marker for testing malignant transformation and metastatic competence. Biophysical Journal, 88, 3689–3698.

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Asnacios, A., Desprat, N., and Guiroy, A. (2006). Microplates-based rheometer for a single living cell. Review of Scientific Instruments 77.

  12. 12.

    Cross, S. E., Jin, Y. S., Rao, J., & Gimzewski, J. K. (2007). Nanomechanical analysis of cells from cancer patients. Nature Nanotechnology, 2, 780–783.

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Fritsch, A., Hockel, M., Kiessling, T., Nnetu, K. D., Wetzel, F., Zink, M., et al. (2010). Are biomechanical changes necessary for tumour progression? Nature Physics, 6, 730–732.

    Article  CAS  Google Scholar 

  14. 14.

    Pelling, A. E., Dawson, D. W., Carreon, D. M., Christiansen, J. J., Shen, R. R., Teitell, M. A., et al. (2007). Distinct contributions of microtubule subtypes to cell membrane shape and stability. Nanomed-Nanotechnol, 3, 43–52.

    Article  CAS  Google Scholar 

  15. 15.

    Weihs, D., Mason, T. G., and Teitell, M. A. (2007). Effects of cytoskeletal disruption on transport, structure, and rheology within mammalian cells. Physics Fluids 19.

  16. 16.

    Weihs, D., Mason, T. G., & Teitell, M. A. (2006). Bio-microrheology: A frontier in microrheology. Biophysical Journal, 91, 4296–4305.

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Hoffman, B. D., & Crocker, J. C. (2009). Cell mechanics: dissecting the physical responses of cells to force. Annual Review of Biomedical Engineering, 11, 259–288.

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Gal, N., and Weihs, D. (2010). Experimental evidence of strong anomalous diffusion in living cells. Physical Review E 81, 020903(R).

  19. 19.

    Arcizet, D., Meier, B., Sackmann, E., Radler, J. O., and Heinrich, D. (2008). Temporal analysis of active and passive transport in living cells. Physical Review Letter 101.

  20. 20.

    Hoffman, B. D., Massiera, G., Van Citters, K. M., & Crocker, J. C. (2006). The consensus mechanics of cultured mammalian cells. Proceedings of National Academy of Sciences USA, 103, 10259–10264.

    Article  CAS  Google Scholar 

  21. 21.

    Caspi, A., Granek, R., & Elbaum, M. (2000). Enhanced diffusion in active intracellular transport. Physical Review Letters, 85, 5655–5658.

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Yamada, S., Wirtz, D., & Kuo, S. C. (2000). Mechanics of living cells measured by laser tracking microrheology. Biophysical Journal, 78, 1736–1747.

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    Kulkarni, R. P., Castelino, K., Majumdar, A., & Fraser, S. E. (2006). Intracellular transport dynamics of endosomes containing DNA polyplexes along the microtubule network. Biophysical Journal, 90, L42–L44.

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Robert, D., Nguyen, T. H., Gallet, F., and Wilhelm, C. (2010). In vivo determination of fluctuating forces during endosome trafficking using a combination of active and passive microrheology. PLoS ONE 5.

  25. 25.

    Li, Y. X., Schnekenburger, J., and Duits, M. H. G. (2009). Intracellular particle tracking as a tool for tumor cell characterization. Journal of Biomedical Optics 14.

  26. 26.

    Yizraeli, M. L., and Weihs, D. (2011). Time-dependent micromechanical responses of breast cancer cells and adjacent fibroblasts to electric treatment. Cell Biochemistry and Biophysics (in press).

  27. 27.

    Crocker, J. C., & Grier, D. G. (1996). Methods of digital video microscopy for colloidal studies. Journal of Colloid and Interface Science, 179, 298–310.

    Article  CAS  Google Scholar 

  28. 28.

    Brangwynne, C. P., Koenderink, G. H., Weitz, D. A., & MacKintosh, F. C. (2009). Intracellular transport by active diffusion. Trends in Cell Biology, 19, 423–427.

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Saxton, M. J., & Jacobson, K. (1997). Single-particle tracking: Applications to membrane dynamics. Annual Review of Biophysics and Biomolecular Structure, 26, 373–399.

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Metzler, R., & Klafter, J. (2000). The random walk’s guide to anomalous diffusion: a fractional dynamics approach. Physics Reports, 339, 1–77.

    Article  CAS  Google Scholar 

  31. 31.

    Burov, S., Jeon, J. H., Metzler, R., & Barkai, E. (2011). Single particle tracking in systems showing anomalous diffusion: the role of weak ergodicity breaking. Physical Chemistry Chemical Physics: PCCP, 13, 1800–1812.

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Brangwynne, C. P., Koenderink, G. H., MacKintosh, F. C., and Weitz, D. A. (2008). Nonequilibrium microtubule fluctuations in a model cytoskeleton. Physical Review Letter 100.

  33. 33.

    Savin, T., & Doyle, P. S. (2005). Static and dynamic errors in particle tracking microrheology. Biophysical Journal, 88, 623–638.

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Castiglione, P., Mazzino, A., Muratore-Ginanneschi, P., & Vulpiani, A. (1999). On strong anomalous diffusion. Physica D: Nonlinear Phenomena, 134, 75–93.

    Article  Google Scholar 

  35. 35.

    Ferrari, R., Manfroi, A. J., & Young, W. R. (2001). Strongly and weakly self-similar diffusion. Physica D: Nonlinear Phenomena, 154, 111–137.

    Article  CAS  Google Scholar 

  36. 36.

    Oppong, F. K., & de Bruyn, J. R. (2007). Diffusion of microscopic tracer particles in a yield-stress fluid. J Non-Newton Fluid, 142, 104–111.

    Article  CAS  Google Scholar 

  37. 37.

    Girard, K. D., Kuo, S. C., & Robinson, D. N. (2006). Dictyostelium myosin II mechanochemistry promotes active behavior of the cortex on long time scales. Proceedings of National Academy of Sciences USA, 103, 2103–2108.

    Article  CAS  Google Scholar 

  38. 38.

    Raupach, C., Zitterbart, D. P., Mierke, C. T., Metzner, C., Muller, F. A., and Fabry, B. (2007). Stress fluctuations and motion of cytoskeletal-bound markers. Physical Review E 76.

  39. 39.

    Bronstein, I., Israel, Y., Kepten, E., Mai, S., Shav-Tal, Y., Barkai, E., and Garini, Y. (2009). Transient anomalous diffusion of telomeres in the nucleus of mammalian cells. Physical Review Letter 103.

  40. 40.

    Caspi, A., Granek, R., and Elbaum, M. (2002). Diffusion and directed motion in cellular transport. Physical Review E Statistical, Nonlinear, and Soft Matter Physics 66, 011916.

    Google Scholar 

  41. 41.

    Snider, J., Lin, F., Zahedi, N., Rodionov, V., Yu, C. C., & Gross, S. P. (2004). Intracellular actin-based transport: How far you go depends on how often you switch. Proceedings of National Academy of Sciences USA, 101, 13204–13209.

    Article  CAS  Google Scholar 

  42. 42.

    Umansky, M., and Weihs, D. (2012). Novel algorithm and MATLAB-based program for automated power law analysis of single particle. Time-dependent mean-square displacement. Computer Physics Communications (in press).

  43. 43.

    Lau, A. W. C., Hoffman, B. D., Davies, A., Crocker, J. C., and Lubensky, T. C. (2003). Microrheology, stress fluctuations, and active behavior of living cells. Physical Review Letter 91.

  44. 44.

    Wilhelm, C. (2008). Out-of-equilibrium microrheology inside living cells. Physical Review Letter 101.

  45. 45.

    Kulic, I. M., Brown, A. E., Kim, H., Kural, C., Blehm, B., Selvin, P. R., et al. (2008). The role of microtubule movement in bidirectional organelle transport. Proceedings of National Academy of Sciences USA, 105, 10011–10016.

    Article  CAS  Google Scholar 

  46. 46.

    Li, Q. S., Lee, G. Y. H., Ong, C. N., & Lim, C. T. (2008). AFM indentation study of breast cancer cells. Biochemical and Biophysical Research Communications, 374, 609–613.

    PubMed  Article  CAS  Google Scholar 

  47. 47.

    Mizuno, D., Tardin, C., Schmidt, C. F., & MacKintosh, F. C. (2007). Nonequilibrium mechanics of active cytoskeletal networks. Science, 315, 370–373.

    PubMed  Article  CAS  Google Scholar 

  48. 48.

    Bursac, P., Lenormand, G., Fabry, B., Oliver, M., Weitz, D. A., Viasnoff, V., et al. (2005). Cytoskeletal remodelling and slow dynamics in the living cell. Nature Materials, 4, 557–561.

    PubMed  Article  CAS  Google Scholar 

  49. 49.

    Lin, Y. C., Koenderink, G. H., MacKintosh, F. C., & Weitz, D. A. (2007). Viscoelastic properties of microtubule networks. Macromolecules, 40, 7714–7720.

    Article  CAS  Google Scholar 

  50. 50.

    Pelletier, V., Gal, N., Fournier, P., and Kilfoil, M. L. (2009). Microrheology of Microtubule Solutions and actin-microtubule composite networks. Physical Review Letter 102.

  51. 51.

    Caspi, A., Granek, R., Lachish, A., Zbaida, D., & Elbaum, M. (1998). Semiflexible polymer network: A view from inside. Physical Review Letters, 80, 1106–1109.

    Article  CAS  Google Scholar 

  52. 52.

    Kural, C., Kim, H., Syed, S., Goshima, G., Gelfand, V. I., & Selvin, P. R. (2005). Kinesin and dynein move a peroxisome in vivo: A tug-of-war or coordinated movement? Science, 308, 1469–1472.

    PubMed  Article  CAS  Google Scholar 

  53. 53.

    Lipowsky, R., Klumpp, S., & Nieuwenhuizen, T. M. (2001). Random walks of cytoskeletal motors in open and closed compartments. Physical Review Letters, 87, 108101.

    PubMed  Article  CAS  Google Scholar 

  54. 54.

    Kahana, A., Kenan, G., Feingold, M., Elbaum, M., and Granek, R. (2008). Active transport on disordered microtubule networks: The generalized random velocity model. Physical Review E Statistical Nonlinear Soft Matter Physics 78, 051912.

    Google Scholar 

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Acknowledgments

The study was partially funded by Israeli Ministry of Science and Technology and by the Technion Russel Berrie Nanotechnology Institute. Confocal imaging was performed at the facilities of the Lorry I. Lokey Interdisciplinary Center for Life Sciences and Engineering.

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Correspondence to Daphne Weihs.

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Gal, N., Weihs, D. Intracellular Mechanics and Activity of Breast Cancer Cells Correlate with Metastatic Potential. Cell Biochem Biophys 63, 199–209 (2012). https://doi.org/10.1007/s12013-012-9356-z

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Keywords

  • Particle tracking
  • Cell mechanics
  • Real time imaging in living cells