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.

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Mechano-sensation of cells is an important prerequisite for cellular function, e.g. in the context of cell migration, tissue organisation and morphogenesis. An important mechano-chemical-transducer is the actin cytoskeleton. In fact, previous studies have shown that actin cross-linkers, such as α-actinin-4, exhibit mechanosensitive properties in its binding dynamics to actin polymers. However, to date, a quantitative analysis of tension-dependent binding dynamics in live cells is lacking. Here, we present a new technique that allows to quantitatively characterize the dependence of cross-linking lifetime of actin cross-linkers on mechanical tension in the actin cortex of live cells. We use an approach that combines parallel plate confinement of round cells, fluorescence recovery after photo-bleaching, and a mathematical mean-field model of cross-linker binding. We apply our approach to the actin cross-linker α-actinin-4 and show that the cross-linking time of α-actinin-4 homodimers increases approximately twofold within the cellular range of cortical mechanical tension rendering α-actinin-4 a catch bond in physiological tension ranges.

Cell shape changes are vital for many physiological processes such as cell proliferation, cell migration and morphogenesis. They emerge from an orchestrated interplay of active cellular force generation and passive cellular force response -both crucially influenced by the actin cytoskeleton. To model cellular force response and deformation, cell mechanical models commonly describe the actin cytoskeleton as a contractile isotropic incompressible material. However, in particular at slow frequencies, there is no compelling reason to assume incompressibility as the water content of the cytoskeleton may change. Here we challenge the assumption of incompressibility by comparing computer simulations of an isotropic actin cortex with tunable Poisson ratio to measured cellular force response. Comparing simulation results and experimental data, we determine the Poisson ratio of the cortex in a frequency-dependent manner. We find that the Poisson ratio of the cortex decreases with frequency likely due to actin cortex turnover leading to an over-proportional decrease of shear stiffness at larger time scales. We thus report a trend of the Poisson ratio similar to that of glassy materials, where the frequency-dependence of jamming leads to an analogous effect. arXiv:1912.04927v2 [physics.bio-ph] 14 Dec 2019 2 Side view x z shear dilation C o rtical sh e ll a) b) c) 0 h 0 =14 μm h 0 =12 μm h 0 h 0 =8 μm 0 0.5 1 area shear area dilation area shear h 0 =10 μm h 1 reference shape deformed shapeFigure 1. Elastic uniaxial compression of a cortical shell. a) Cell-mechanical model. b) Left panel: a square-shaped surface element (green) in the elastic reference shape of the shell. Right panel: after a small amount of uniaxial compression through reduction of shell height, the surface element is deformed (deformation is exaggerrated here for illustration purposes). c) Elastic deformation of model cells exhibit a decreasing ratio of area shear to area dilation at decreasing reference cell heights (simulation parameters as in Fig. 2). INTRODUCTIONThe actin cytoskeleton, a cross-linked meshwork of actin polymers, is a key structural element that crucially influences mechanical properties of cells [1]. In fact, for rounded mitotic cells, the mitotic actin cortex, a thin actin cytoskeleton layer attached to the plasma membrane, could be shown to be the dominant mechanical structure in whole-cell deformations [6].In the past, cell mechanical models have been developed to rationalize cell deformation in different biological systems [3, 4]. Commonly, these models describe the actin cytoskeleton as a contractile isotropic incompressible material [5]. The assumption of incompressibility implies a Poisson ratio of 0.5. Incompressibility of the actin cytoskeleton is motivated by incompressibility of water and high water content in the actin cytoskeleton [6]. This assumption is justified for high-frequency deformations as in this case substantial water movement past the elastic scaffold of the polymerized actin meshwork would give rise to strong fri...

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, we show that epithelial mesenchymal transition (EMT), a hallmark of cancer progression and metastasis, gives rise to a cell-cycle dependent cellmechanical switch and enhanced mitotic rounding strength in breast epithelial cells. Furthermore, we show that this cell-mechanical change correlates with a strong EMT-induced change in the activity of Rho GTPases RhoA and Rac1. Accordingly, we identify Rac1 as a cell-cycle dependent regulator of actin cortex mechanics. Our findings hint at a new role of EMT in successful mitotic rounding and division in mechanically confined environments such as a growing tumor.