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Stopping transformed cancer cell growth by rigidity sensing

Nature Materials volume 19, pages 239–250 (2020)Cite this article

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Abstract

A common feature of cancer cells is the alteration of kinases and biochemical signalling pathways enabling transformed growth on soft matrices, whereas cytoskeletal protein alterations are thought to be a secondary issue. However, we report here that cancer cells from different tissues can be toggled between transformed and rigidity-dependent growth states by the absence or presence of mechanosensory modules, respectively. In various cancer lines from different tissues, cells had over tenfold fewer rigidity-sensing contractions compared with normal cells from the same tissues. Restoring normal levels of cytoskeletal proteins, including tropomyosins, restored rigidity sensing and rigidity-dependent growth. Further depletion of other rigidity sensor proteins, including myosin IIA, restored transformed growth and blocked sensing. In addition, restoration of rigidity sensing to cancer cells inhibited tumour formation and changed expression patterns. Thus, the depletion of rigidity-sensing modules through alterations in cytoskeletal protein levels enables cancer cell growth on soft surfaces, which is an enabling factor for cancer progression.

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Fig. 1: Fundamental differences between normal and transformed cells during initial spreading.
Fig. 2: Transformed cells lack rigidity sensing and rigidity sensor proteins.
Fig. 3: Myosin IIA in Cos7 cells enables normal growth, but Tpm 2.1 silencing restores transformation.
Fig. 4: Tpm 2.1 in MDA-MB-231 enables normal growth but myosin IIA depletion restores transformation.
Fig. 5: High levels of Tpm 3 (3.1 and 3.2) inhibit cell rigidity sensing.
Fig. 6: Restoration of rigidity sensing in transformed cells blocks tumour formation in vivo.

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Data supporting the findings of this study are available within the article and from the corresponding author upon reasonable request;

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Acknowledgements

The authors thank J.P. Thiery, P. Gunning, N.C. Gauthier and J. Kadrmas for critical reading of the manuscript. We thank D. Lim Gkeok Stzuan (NUHS) and A. Koh Pei Fern (CSI) for their kind help with H&E staining. We thank the members of Sheetz and Bershadsky laboratories for their kind help. This research was supported by funding to the Mechanobiology Institute, National University of Singapore. B.Y. was supported by the NUS grant ‘Activation of Apotosis by Soft Surfaces’ (no. R-714-000-112-133). H.W. is a David and Inez Myers Career Advancement Chair in Life Sciences fellow. M.P.S. is supported by NIH and NUS grants and the Mechanobiology Institute, National University of Singapore.

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Author notes

  1. Naotaka Nakazawa

    Present address: Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto, Japan

Authors and Affiliations

  1. Mechanobiology Institute, National University of Singapore, Singapore, Singapore

    Bo Yang, Naotaka Nakazawa & Michael P. Sheetz

  2. Department of Genetics and Developmental Biology, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel of Technology, Haifa, Israel

    Haguy Wolfenson

  3. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore

    Vin Yee Chung & Ruby Yun-Ju Huang

  4. Department of Mechanical Engineering, Columbia University, New York, NY, USA

    Shuaimin Liu & Junqiang Hu

  5. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Ruby Yun-Ju Huang

  6. Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Ruby Yun-Ju Huang

  7. Department of Biological Sciences, Columbia University, New York, NY, USA

    Michael P. Sheetz

  8. Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA

    Michael P. Sheetz

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Contributions

B.Y. and M.P.S. conceived the study and designed the experiments. B.Y. and N.N. performed the experiments. V.Y.C. and R.Y.-J.H performed the CAM experiments and analysed data. S.L. wrote Matlab codes for data analysis. J.H. provided fabrication moulds. B.Y., H.W. and M.P.S wrote and prepared the manuscript.

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Correspondence to Michael P. Sheetz.

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Yang, B., Wolfenson, H., Chung, V.Y. et al. Stopping transformed cancer cell growth by rigidity sensing. Nat. Mater. 19, 239–250 (2020). https://doi.org/10.1038/s41563-019-0507-0

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