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Actin as a Target to Reduce Cell Invasiveness in Initial Stages of Metastasis

Abstract

We demonstrate the relative roles of the cell cytoskeleton, and specific importance of actin in facilitating mechanical aspects of metastatic invasion. A crucial step in metastasis, the typically lethal spread of cancer to distant body-sites, is cell invasion through dense tissues composed of extracellular matrix and various non-cancerous cells. Cell invasion requires cell-cytoskeleton remodeling to facilitate dynamic morphological changes and force application. We have previously shown invasive cell subsets in heterogeneous samples can rapidly (2 h) and forcefully indent non-degradable, impenetrable, synthetic gels to cell-scale depths. The amounts of indenting cells and their attained depths provide the mechanical invasiveness of the sample, which as we have shown agrees with the in vitro metastatic potential and the in vivo metastatic risk in humans. To identify invasive force-application mechanisms, we evaluated changes in mechanical invasiveness following chemical perturbations targeting the structure and function of cytoskeleton elements and associated proteins. We evaluate effects on short-term (2-hr) indentations of single, well-spaced or closely situated cells as compared to long-time-scale Boyden chamber migration. We show that actomyosin inhibition may be used to reduce (mechanical) invasiveness of single or collectively invading cells, while actin-disruption may induce escape-response of treated single-cells, which may promote metastasis.

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Acknowledgments

The authors thank Mr. Yam Horesh for his assistance with the cell viability determination. The work was partially funded by the Elias Fund for Medical Research, the Polak Fund for Applied Research, and the Samuel H. Born Fund for Biomedical Research.

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No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript.

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Correspondence to Daphne Weihs.

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Alvarez-Elizondo, M.B., Merkher, Y., Shleifer, G. et al. Actin as a Target to Reduce Cell Invasiveness in Initial Stages of Metastasis. Ann Biomed Eng 49, 1342–1352 (2021). https://doi.org/10.1007/s10439-020-02679-7

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Keywords

  • Mechanobiology
  • Metastatic potential
  • Cytoskeleton
  • Cancer invasion
  • Cell migration and invasion