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The nanomechanical signature of breast cancer

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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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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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.

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Correspondence to Roderick Y. H. Lim.

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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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