Abstract
To undergo mitosis successfully, most animal cells need to acquire a round shape to provide space for the mitotic spindle. This mitotic rounding relies on mechanical deformation of surrounding tissue and is driven by forces emanating from actomyosin contractility. Cancer cells are able to maintain successful mitosis in mechanically challenging environments such as the increasingly crowded environment of a growing tumor, thus, suggesting an enhanced ability of mitotic rounding in cancer. Here, it is shown that the epithelial–mesenchymal transition (EMT), a hallmark of cancer progression and metastasis, gives rise to cell‐mechanical changes in breast epithelial cells. These changes are opposite in interphase and mitosis and correspond to an enhanced mitotic rounding strength. Furthermore, it is shown that cell‐mechanical changes correlate with a strong EMT‐induced change in the activity of Rho GTPases RhoA and Rac1. Accordingly, it is found that Rac1 inhibition rescues the EMT‐induced cortex‐mechanical phenotype. The findings hint at a new role of EMT in successful mitotic rounding and division in mechanically confined environments such as a growing tumor.
Highlights
Most animal cells adopt an approximately spherical shape when entering mitosis[1]
Our observation that post-Epithelial-mesenchymal transition (EMT) interphase cells have a softer actin cytoskeleton is in agreement with a study by Osborne et al that reported softening of adherent cells upon EMT52 and with reports that metastatic cancer cells are on average softer than healthy and non-metastatic cells[20,53,54,55]
We could confirm enhanced mitotic rounding in post-EMT conditions by our observation of increased roundness of mitotic cells in spheroids growing in non-degradable Peg-Heparin hydrogels (Figure 5c)
Summary
Most animal cells adopt an approximately spherical shape when entering mitosis[1]. This process has been termed mitotic rounding. At the onset of mitosis, cortical contractility was found to be upregulated giving rise to an increased cell surface tension which drives the mitotic cell into a spherical shape[8,9]. This physical picture is consistent with reports that mitotic rounding relies on RhoA7,12,13 – a major actomyosin regulator in the cell. We determine mechanical changes of the actin cortex of interphase cells upon EMT; mechanics of interphase cells may critically influence mitotic rounding as interphase cells are a major constituent of the surrounding of a mitotic cell which needs to be deformed in the process of rounding (Figure 1). We give evidence that EMT, as well as Rac[1] activity changes induce actual changes in mitotic rounding in spheroids embedded in mechanically confining, covalently crosslinked hydrogels[25]
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