The metastatic cancer cell cortex: An adaptation to enhance robust cell division in novel environments?

Matthews, Helen K.; Baum, Buzz

doi:10.1002/bies.201200109

Cited by 17 publications

(10 citation statements)

References 31 publications

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“…Studies of multicellular spheroids indicate that the mechanical pressure of the tissue environment can impair cell proliferation (33,34). Moreover, it has been predicted that cells in stiffer or more densely packed tissue environments, such as of an overgrown tumor, would require a more robust cell cortex and mitotic rounding response (9,35). Indeed, although strategies for chemical perturbation of cell division have been pursued for decades (36), the advent of mechanical approaches opens the door to studies of physical perturbation.…”

Section: Discussionmentioning

confidence: 99%

Mechanical control of mitotic progression in single animal cells

Cattin

Düggelin

Martínez-Martín

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Despite the importance of mitotic cell rounding in tissue development and cell proliferation, there remains a paucity of approaches to investigate the mechanical robustness of cell rounding. Here we introduce ion beam-sculpted microcantilevers that enable precise force-feedback-controlled confinement of single cells while characterizing their progression through mitosis. We identify three force regimes according to the cell response: small forces (∼5 nN) that accelerate mitotic progression, intermediate forces where cells resist confinement (50-100 nN), and yield forces (>100 nN) where a significant decline in cell height impinges on microtubule spindle function, thereby inhibiting mitotic progression. Yield forces are coincident with a nonlinear drop in cell height potentiated by persistent blebbing and loss of cortical F-actin homogeneity. Our results suggest that a buildup of actomyosin-dependent cortical tension and intracellular pressure precedes mechanical failure, or herniation, of the cell cortex at the yield force. Thus, we reveal how the mechanical properties of mitotic cells and their response to external forces are linked to mitotic progression under conditions of mechanical confinement.

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Section: Discussionmentioning

confidence: 99%

Mechanical control of mitotic progression in single animal cells

Cattin

Düggelin

Martínez-Martín

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The altered mechanical micro-environment in tumors affects multiple processes including cell invasion ( Levental et al, 2009 ; Acerbi et al, 2015 ) and phenotypic state ( Wei et al, 2015 ), but likely also impacts the cell division process. We have previously proposed that completing cell division in such an altered mechanical environment presents a challenge that could be overcome by enhanced mitotic rounding in cancer cells ( Matthews and Baum, 2012 ). This is supported by the frequent observation of highly rounded mitotic cells in cancer samples and tumoroids ( Figure 3C ).…”

Section: Mitotic Rounding and Stiffening In Diseased Tissuementioning

confidence: 99%

The Mechanics of Mitotic Cell Rounding

Taubenberger

Baum

Matthews

2020

Front. Cell Dev. Biol.

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109

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When animal cells enter mitosis, they round up to become spherical. This shape change is accompanied by changes in mechanical properties. Multiple studies using different measurement methods have revealed that cell surface tension, intracellular pressure and cortical stiffness increase upon entry into mitosis. These cell-scale, biophysical changes are driven by alterations in the composition and architecture of the contractile actomyosin cortex together with osmotic swelling and enable a mitotic cell to exert force against the environment. When the ability of cells to round is limited, for example by physical confinement, cells suffer severe defects in spindle assembly and cell division. The requirement to push against the environment to create space for spindle formation is especially important for cells dividing in tissues. Here we summarize the evidence and the tools used to show that cells exert rounding forces in mitosis in vitro and in vivo, review the molecular basis for this force generation and discuss its function for ensuring successful cell division in single cells and for cells dividing in normal or diseased tissues.

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“…[ 14–18 ] Thus, it has been hypothesized that the actin cortex of cancer cells exhibits oncogenic adaptations that allow for ongoing mitotic rounding and division inside tumors. [ 19 ] In fact, it was shown that the human oncogene Ect2 contributes to mitotic rounding through RhoA activation [ 7,10 ] and that Ras overexpression promotes mitotic rounding. [ 20 ]…”

Section: Introductionmentioning

confidence: 99%

EMT‐Induced Cell‐Mechanical Changes Enhance Mitotic Rounding Strength

et al. 2020

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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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The metastatic cancer cell cortex: An adaptation to enhance robust cell division in novel environments?

Cited by 17 publications

References 31 publications

Mechanical control of mitotic progression in single animal cells

Mechanical control of mitotic progression in single animal cells

The Mechanics of Mitotic Cell Rounding

EMT‐Induced Cell‐Mechanical Changes Enhance Mitotic Rounding Strength

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