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The nanomechanical signature of breast cancer

Nature Nanotechnology volume 7, pages 757–765 (2012)Cite this article

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Abstract

Cancer initiation and progression follow complex molecular and structural changes in the extracellular matrix and cellular architecture of living tissue. However, it remains poorly understood how the transformation from health to malignancy alters the mechanical properties of cells within the tumour microenvironment. Here, we show using an indentation-type atomic force microscope (IT-AFM) that unadulterated human breast biopsies display distinct stiffness profiles. Correlative stiffness maps obtained on normal and benign tissues show uniform stiffness profiles that are characterized by a single distinct peak. In contrast, malignant tissues have a broad distribution resulting from tissue heterogeneity, with a prominent low-stiffness peak representative of cancer cells. Similar findings are seen in specific stages of breast cancer in MMTV-PyMT transgenic mice. Further evidence obtained from the lungs of mice with late-stage tumours shows that migration and metastatic spreading is correlated to the low stiffness of hypoxia-associated cancer cells. Overall, nanomechanical profiling by IT-AFM provides quantitative indicators in the clinical diagnostics of breast cancer with translational significance.

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Figure 1: Nanomechanical signatures of human breast tissue.
Figure 2: Stiffness varies from core to periphery in human cancer biopsies.
Figure 3: Correlating the nanomechanical response with tumour progression in MMTV-PyMT mice.
Figure 4: Correlating local nanomechanical properties and ECM structure in late cancer.
Figure 5: Stiffness profiles of primary tumour and lung metastasis reveal a common phenotype.
Figure 6: Dissemination of hypoxic cancer cells increases with tumour progression.

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References

  1. Ingber, D. E. et al. Cellular tensegrity—exploring how mechanical changes in the cytoskeleton regulate cell-growth, migration, and tissue pattern during morphogenesis. Int. Rev. Cytol. 150, 173–224 (1994).

    Article  CAS  Google Scholar 

  2. Park, C. C., Bissell, M. J. & Barcellos-Hoff, M. H. The influence of the microenvironment on the malignant phenotype. Mol. Med. Today 6, 324–329 (2000).

    Article  CAS  Google Scholar 

  3. Needham, D. Possible role of cell cycle-dependent morphology, geometry, and mechanical-properties in tumor-cell metastasis. Cell Biophys. 18, 99–121 (1991).

    Article  CAS  Google Scholar 

  4. Paszek, M. J. & Weaver, V. M. The tension mounts: mechanics meets morphogenesis and malignancy. J. Mammary Gland Biol. 9, 325–342 (2004).

    Article  Google Scholar 

  5. Kumar, S. & Weaver, V. Mechanics, malignancy, and metastasis: the force journey of a tumor cell. Cancer Metast. Rev. 28, 113–127 (2009).

    Article  Google Scholar 

  6. Kass, L., Erler, J. T., Dembo, M. & Weaver, V. M. Mammary epithelial cell: influence of extracellular matrix composition and organization during development and tumorigenesis. Int. J. Biochem. Cell B 39, 1987–1994 (2007).

    Article  CAS  Google Scholar 

  7. Butcher, D. T., Alliston, T. & Weaver, V. M. A tense situation: forcing tumour progression. Nature Rev. Cancer 9, 108–122 (2009).

    Article  CAS  Google Scholar 

  8. Sinkus, R. et al. High-resolution tensor MR elastography for breast tumour detection. Phys. Med. Biol. 45, 1649–1664 (2000).

    Article  CAS  Google Scholar 

  9. Paszek, M. J. et al. Tensional homeostasis and the malignant phenotype. Cancer Cell 8, 241–254 (2005).

    Article  CAS  Google Scholar 

  10. Levental, K. R. et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139, 891–906 (2009).

    Article  CAS  Google Scholar 

  11. Rosenbluth, M. J., Lam, W. A. & Fletcher, D. A. Force microscopy of nonadherent cells: a comparison of leukemia cell deformability. Biophys. J. 90, 2994–3003 (2006).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  13. Lekka, M. et al. Elasticity of normal and cancerous human bladder cells studied by scanning force microscopy. Eur. Biophys. J. Biophy. 28, 312–316 (1999).

    Article  CAS  Google Scholar 

  14. Ward, K. A., Li, W. I., Zimmer, S. & Davis, T. Viscoelastic properties of transformed-cells—role in tumor-cell progression and metastasis formation. Biorheology 28, 301–313 (1991).

    Article  CAS  Google Scholar 

  15. Lam, W. A., Rosenbluth, M. J. & Fletcher, D. A. Chemotherapy exposure increases leukemia cell stiffness. Blood 109, 3505–3508 (2007).

    Article  CAS  Google Scholar 

  16. Guck, J. et al. Optical deformability as an inherent cell marker for testing malignant transformation and metastatic competence. Biophys. J. 88, 3689–3698 (2005).

    Article  CAS  Google Scholar 

  17. Suresh, S. Biomechanics and biophysics of cancer cells. Acta Mater. 55, 3989–4014 (2007).

    Article  CAS  Google Scholar 

  18. Lekka, M. et al. Cancer cell detection in tissue sections using AFM. Arch. Biochem. Biophys. 518, 151–156 (2012).

    Article  CAS  Google Scholar 

  19. Weaver, V. M. et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139, 891–906 (2009).

    Article  Google Scholar 

  20. Erler, J. T. & Weaver, V. M. Three-dimensional context regulation of metastasis. Clin. Exp. Metastasis 26, 35–49 (2009).

    Article  Google Scholar 

  21. Weaver, V. M., DuFort, C. C. & Paszek, M. J. Balancing forces: architectural control of mechanotransduction. Nature Rev. Mol. Cell. Biol. 12, 308–319 (2011).

    Google Scholar 

  22. Lin, E. Y. et al. Progression to malignancy in the polyoma middle T oncoprotein mouse breast cancer model provides a reliable model for human diseases. Am. J. Pathol. 163, 2113–2126 (2003).

    Article  Google Scholar 

  23. Lundin, M., Lundin, J., Helin, H. & Isola, J. A digital atlas of breast histopathology: an application of web based virtual microscopy. J. Clin. Pathol. 57, 1288–1291 (2004).

    Article  CAS  Google Scholar 

  24. Weaver, V. M. et al. Tensional homeostasis and the malignant phenotype. Cancer Cell 8, 241–254 (2005).

    Article  Google Scholar 

  25. Egeblad, M. & Werb, Z. New functions for the matrix metalloproteinases in cancer progression. Nature Rev. Cancer 2, 161–174 (2002).

    Article  CAS  Google Scholar 

  26. Albrechtsen, R., Nielsen, M., Wewer, U., Engvall, E. & Ruoslahti, E. Basement membrane changes in breast cancer detected by immunohistochemical staining for laminin. Cancer Res. 41, 5076–5081 (1981).

    CAS  Google Scholar 

  27. Guy, C. T., Cardiff, R. D. & Muller, W. J. Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol. Cell Biol. 12, 954–961 (1992).

    Article  CAS  Google Scholar 

  28. Fantozzi, A. & Christofori, G. Mouse models of breast cancer metastasis. Breast Cancer Res. 8, 212 (2006).

    Article  Google Scholar 

  29. Guppy, M. The hypoxic core: a possible answer to the cancer paradox. Biochem. Biophys. Res. Commun. 299, 676–680 (2002).

    Article  CAS  Google Scholar 

  30. Sedwick, C. Valerie Weaver: overcoming cancer's stiff resistance. J. Cell. Biol. 193, 802–803 (2011).

    Article  Google Scholar 

  31. Lopez, J. I., Kang, I., You, W. K., McDonald, D. M. & Weaver, V. M. In situ force mapping of mammary gland transformation. Integr. Biol. (Camb.) 3, 910–921 (2011).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  33. Alcaraz, J. et al. Collective epithelial cell invasion overcomes mechanical barriers of collagenous extracellular matrix by a narrow tube-like geometry and MMP14-dependent local softening. Integr. Biol. (Camb.) 3, 1153–1166 (2011).

    Article  CAS  Google Scholar 

  34. Stolz, M. et al. Early detection of aging cartilage and osteoarthritis in mice and patient samples using atomic force microscopy. Nature Nanotech. 4, 186–192 (2009).

    Article  CAS  Google Scholar 

  35. Thomas, A. et al. Real-time elastography—an advanced method of ultrasound: first results in 108 patients with breast lesions. Ultrasound Obst. Gyn. 28, 335–340 (2006).

    Article  CAS  Google Scholar 

  36. Burnside, E. S. et al. Differentiating benign from malignant solid breast masses with US strain imaging. Radiology 245, 401–410 (2007).

    Article  Google Scholar 

  37. Xu, H. Y. et al. Axial-shear strain imaging for differentiating benign and malignant breast masses. Ultrasound Med. Biol. 36, 1813–1824 (2010).

    Article  Google Scholar 

  38. Wong, C. C. L. et al. Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation. Proc. Natl Acad. Sci. USA 108, 16369–16374 (2011).

    Article  CAS  Google Scholar 

  39. Erler, J. T. et al. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 440, 1222–1226 (2006).

    Article  CAS  Google Scholar 

  40. Fritsch, A. et al. Are biomechanical changes necessary for tumour progression? Nature Phys. 6, 730–732 (2010).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  42. Erler, J. T., Jeffrey, S. S. & Giaccia, A. J. Hypoxia promotes invasion and metastasis of breast cancer cells by increasing lysyl oxidase expression. Breast Cancer Res. 7, S57 (2005).

    Article  Google Scholar 

  43. Sader, J. E., Larson, I., Mulvaney, P. & White, L. R. Method for the calibration of atomic-force microscope cantilevers. Rev. Sci. Instrum. 66, 3789–3798 (1995).

    Article  CAS  Google Scholar 

  44. Oliver, W. C. & Pharr, G. M. An improved technique for determining hardness and elastic-modulus using load and displacement sensing indentation experiments. J. Mater. Res. 7, 1564–1583 (1992).

    Article  CAS  Google Scholar 

  45. Plodinec, M., Loparic, M. & Aebi, U. Atomic force microscopy for biological imaging and mechanical testing across length scales. Cold Spring Harb. Protoc. 2010, pdb top86 (2010).

  46. Loparic, M. et al. Micro- and nanomechanical analysis of articular cartilage by indentation-type atomic force microscopy: validation with a gel-microfiber composite. Biophys. J. 98, 2731–2740 (2010).

    Article  CAS  Google Scholar 

  47. Plodinec, M. et al. The nanomechanical properties of rat fibroblasts are modulated by interfering with the vimentin intermediate filament system. J. Struct. Biol. 174, 476–484 (2011).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank U. Mueller for excising tissues from MMTV-PyMT mice, T. Nguyen and P. Hirschmann for technical assistance with histology and IHC, and R. Suetterlin for advice on IHC. B. Bircher is acknowledged for his contribution to AFM data analysis, T. Pfändler for logistic support concerning clinical samples and A. Roulier for help with the drawing in Fig. 1. The authors also thank U. Sauder for SEM sample preparation, D. Mathys for SEM imaging and P. Demougin for RNA extraction. This work is funded by the National Centre of Competence in Research ‘Nanoscale Science’, Swiss National Science Foundation (to C-A.S.), and the Commission for Technology and Innovation (CTI) supporting university–industry partnerships (Project 11977.2 PFNM-NM within the project ARTIDIS ‘Automated and Reliable Tissue Diagnostics’ awarded to R.Y.H.L in partnership with Nanosurf AG). R.Z.D. is supported by Krebsliga Beider Basel (grant no. 22-2010). The laboratory of M.B-A. is supported by the Novartis Research Foundation, the European Research Council (ERC starting grant no. 243211-PTPsBDC), the Swiss Cancer League and the Krebsliga Beider Basel.

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Author notes

  1. Marko Loparic, Christophe A. Monnier, Ellen C. Obermann and Rosanna Zanetti-Dallenbach: These authors contributed equally to this work

Authors and Affiliations

  1. Biozentrum and the Swiss Nanoscience Institute, University of Basel, Basel, 4056, Switzerland

    Marija Plodinec, Marko Loparic, Christophe A. Monnier, Philipp Oertle, Janne T. Hyotyla & Roderick Y. H. Lim

  2. Maurice E. Mueller Institute for Structural Biology, Biozentrum, University of Basel, Basel, 4056, Switzerland

    Marija Plodinec, Marko Loparic, Ueli Aebi & Cora-Ann Schoenenberger

  3. Institute of Pathology, University Hospital Basel, Basel, 4031, Switzerland

    Ellen C. Obermann

  4. Department of Gynecology and Gynecological Oncology, University Hospital Basel, University of Basel, Basel, 4031, Switzerland

    Rosanna Zanetti-Dallenbach

  5. Mechanisms of Cancer, Friedrich Miescher Institute for Biomedical Research, Basel, 4058, Switzerland

    Mohamed Bentires-Alj

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Contributions

M.P., R.Y.H.L. and C-A.S. conceived the study and designed experiments. M.P., M.L. and R.Y.H.L. developed all customized hardware and software solutions for AFM. M.P. and E.C.O. performed pathohistological and IHC analysis of human and murine tissues. R.Z.D. recruited patients and provided human biopsies. M.P., C.A.M. and P.O. performed AFM experiments. M.P., M.L, C.A.M., J.T.H., P.O. and R.Y.H.L. analysed AFM data. M.B-A. provided MMTV-PyMT mice and was involved in the analysis of murine tissues. M.P., U.A., R.Y.H.L. and C-A.S. wrote the paper. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Roderick Y. H. Lim.

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Competing interests

The University of Basel has filed patents on the technology and intellectual property related to this work based on the inventions of M.P., M.L. and R.Y.H.L.

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Plodinec, M., Loparic, M., Monnier, C. et al. The nanomechanical signature of breast cancer. Nature Nanotech 7, 757–765 (2012). https://doi.org/10.1038/nnano.2012.167

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