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Solid stress and elastic energy as measures of tumour mechanopathology

Abstract

Solid stress and tissue stiffness affect tumour growth, invasion, metastasis and treatment. Unlike stiffness, which can be precisely mapped in tumours, the measurement of solid stresses is challenging. Here, we show that 2D spatial maps of the solid stress and the resulting elastic energy in excised or in situ tumours with arbitrary shapes and a wide range of sizes can be obtained via three distinct and quantitative techniques that rely on the measurement of tissue displacement after disruption of the confining structures. Application of these methods in models of primary tumours and metastasis revealed that (i) solid stress depends on both cancer cells and their microenvironments, (ii) solid stress increases with tumour size and (iii) mechanical confinement by the surrounding tissue substantially contributes to intratumoral solid stress. Further study of the genesis and consequences of solid stress, facilitated by the engineering principles presented here, may lead to new discoveries and therapies.

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Figure 1: 2D maps of solid stress in tumours.
Figure 2: Solid stress and elastic energy in primary versus metastatic tumours.
Figure 3: Creating tumour slices provides a sensitive measure of the solid stress that is applicable to a wide range of specimen sizes.
Figure 4: Evolution of solid stress and stiffness as a function of tumour size.
Figure 5: In situ measurements of solid stress.

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Acknowledgements

We thank S. Roberge, C. Smith, J. Kahn and M. Duquette for technical assistance. We also thank P. Huang, N. Bardeesy and T. Irimura for providing MMTV-M3C, AK4.4 and SL4 cells, respectively. This work was supported in part by funding from the National Cancer Institute (P01-CA080124), an NCI Outstanding Investigator Award (R35-CA197743) and a Department of Defense Breast Cancer Research Innovator award (W81XWH-10-1-0016) to R.K.J., a DP2 OD008780 to T.P.P., a R01 grant (HL128168) to L.L.M., T.P.P. and J.W.B., a Susan G. Komen Foundation Fellowship (PDF14301739) to G.S., a National Institutes of Health award (F31HL126449) to M.D., and an UNCF-Merck Science Initiative Postdoctoral Fellowship, Burroughs Wellcome Fund Postdoctoral Enrichment Program Award and a NCI grant (F32CA183465) to D.J.

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H.T.N. and R.K.J. designed the study; H.T.N., H.L., G.S., M.D., D.J., N.R., J.I., K.J. performed the research; H.T.N., H.L., G.S., M.D., D.J., N.R., J.I., V.P.C., K.J., J.D.M., V.A., T.P.P., D.F., Y.B., F.J.H., A.J.G., J.W.B., L.L.M. and R.K.J. analysed the data; H.T.N., M.D., G.S., V.P.C., L.L.M. and R.K.J. wrote the manuscript.

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Correspondence to Rakesh K. Jain.

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Competing interests

R.K.J. received consultant fees from Ophthotech, SPARC, SynDevRx and XTuit. R.K.J. owns equity in Enlight, Ophthotech, SynDevRx and XTuit, and serves on the Board of Directors of XTuit and the Boards of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, the Tekla Healthcare Opportunities Fund and the Tekla World Healthcare Fund. No reagents or funding from these companies were used in these studies.

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Nia, H., Liu, H., Seano, G. et al. Solid stress and elastic energy as measures of tumour mechanopathology. Nat Biomed Eng 1, 0004 (2017). https://doi.org/10.1038/s41551-016-0004

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