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Linking cell mechanical memory and cancer metastasis

Nature Reviews Cancer volume 24, pages 216–228 (2024)Cite this article

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Abstract

Metastasis causes most cancer-related deaths; however, the efficacy of anti-metastatic drugs is limited by incomplete understanding of the biological mechanisms that drive metastasis. Focusing on the mechanics of metastasis, we propose that the ability of tumour cells to survive the metastatic process is enhanced by mechanical stresses in the primary tumour microenvironment that select for well-adapted cells. In this Perspective, we suggest that biophysical adaptations favourable for metastasis are retained via mechanical memory, such that the extent of memory is influenced by both the magnitude and duration of the mechanical stress. Among the mechanical cues present in the primary tumour microenvironment, we focus on high matrix stiffness to illustrate how it alters tumour cell proliferation, survival, secretion of molecular factors, force generation, deformability, migration and invasion. We particularly centre our discussion on potential mechanisms of mechanical memory formation and retention via mechanotransduction and persistent epigenetic changes. Indeed, we propose that the biophysical adaptations that are induced by this process are retained throughout the metastatic process to improve tumour cell extravasation, survival and colonization in the distant organ. Deciphering mechanical memory mechanisms will be key to discovering a new class of anti-metastatic drugs.

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Fig. 1: Tumour cell biophysical adaptations in response to the increase in matrix stiffness during primary tumour development.
Fig. 2: Tumour cell mechanosensing, mechanotransduction and mechanical memory of matrix stiffness imprinted through persistent epigenetic changes.
Fig. 3: Mechanically induced tumour cell biophysical adaptations acquired in the primary tumour and retained in the distant organ foster extravasation, avoidance of dormancy and secondary site colonization.

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Acknowledgements

The authors thank J. Godfrey (MIT Koch Institute for Integrative Cancer Research) for his valuable and insightful comments that helped to improve this article. E. Cambria was supported by an Early Postdoc Mobility fellowship from the Swiss National Science Foundation and a postdoctoral fellowship from the Ludwig Center at MIT Koch Institute for Integrative Cancer Research. G.S.O. received funding from Amgen, Inc., and an American Italian Cancer Foundation Postdoctoral Fellowship. S.E.S. was supported by fellowship K00CA212227 from the National Cancer Institute, NIH. This work was supported by a grant from the National Cancer Institute (U54-CA261694).

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Authors and Affiliations

  1. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

    Elena Cambria, Mark F. Coughlin, Giovanni S. Offeddu, Sarah E. Shelton & Roger D. Kamm

  2. Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

    Marie A. Floryan & Roger D. Kamm

  3. Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA

    Sarah E. Shelton

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Contributions

E.C., M.F.C., M.A.F., G.S.O. and S.E.S. researched data for the article. All authors contributed substantially to discussion of the content. E.C., M.F.C., M.A.F., G.S.O. and S.E.S. wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Elena Cambria or Roger D. Kamm.

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Competing interests

R.D.K. is a co-founder of AIM Biotech, a company that markets microfluidic technologies and receives research support from Amgen, AbbVie, Boehringer-Ingelheim, GSK, Novartis, Roche, Takeda, Eisai, EMD Serono and Visterra. None of these activities is related to the content of this article. The other authors declare no competing interests.

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Glossary

Atomic force microscopy

A technique that imposes a small, local deformation to a sample to probe mechanical properties.

Compressive stresses

The component of stress that pushes on a surface to shorten or squeeze a material in the direction perpendicular to the surface.

Elastic modulus

The slope of the stress–strain relationship that gives a quantitative measurement of material stiffness.

Shear wave elastography

A technique that uses sound to induce shear deformation in a material to quantify mechanical properties.

Strain-stiffening

A phenomenon whereby the elastic modulus of a material increases with deformation.

Tensile stresses

The component of stress that pulls on a surface to elongate a material in the direction perpendicular to the surface.

Traction forces

Forces exerted tangential to a substrate to generate motion.

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Cambria, E., Coughlin, M.F., Floryan, M.A. et al. Linking cell mechanical memory and cancer metastasis. Nat Rev Cancer 24, 216–228 (2024). https://doi.org/10.1038/s41568-023-00656-5

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