The size-speed-force relationship governs migratory cell response to tumorigenic factors

Leal‐Egaña, Aldo; Letort, Gaëlle; Martiel, Jean‐Louis; Christ, Andreas; Vignaud, Timothée; Roelants, Caroline; Filhol, Odile; Théry, Manuel

doi:10.1091/mbc.e16-10-0694

Cited by 32 publications

(32 citation statements)

References 86 publications

(75 reference statements)

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“…In addition, we found that E/M cells had higher migratory properties than M cells, which is consistent with recent in vivo data showing that E/M cells can be found at the invasive front of primary tumors (Pastushenko et al, 2018). The correlation between low contractility and fast migration is consistent with our previous observation that fast migrating cells generate low traction forces (Leal-Egaña et al, 2017).…”

Section: The Initiation Of Emt and Establishment Of The Intermediate supporting

confidence: 93%

“…Leal-Egaña et al, 2017). Consistent with the observed levels of cell traction forces (Figure 4c,d) E/M cells migrated faster than E cells, whereas M cells migrated slower(Figure 6e).…”

supporting

confidence: 88%

“…Therefore the low-contractile-force phenotype of E/M cells may also be correlated with stemness. This is suppoted by the observations that the down-regulation of CK2β in mammary epithelial cells induces the expression of stemness markers (Duchemin-Pelletier et al, 2017), mechanical relaxation (Tseng et al, 2011) and the acquisition of high migration velocities (Leal-Egaña et al, 2017). This correlation between stemness and the low-contractile-force phenotype also echoes the widely-used Rho kinase inhibitor Y27632 to maintain the undifferentiated growth of pluripotent stem cells in culture in culture media; an inhibitor which is also potently relaxes acto-myosin contractility (Gauthaman et al, 2010;Pakzad et al, 2010).…”

Section: The Initiation Of Emt and Establishment Of The Intermediate mentioning

confidence: 99%

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Biophysical properties of intermediate states of EMT outperform both epithelial and mesenchymal states

Margaron

Nagai

Guyon

et al. 2019

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Potential metastatic cells can dissociate from a primary breast tumor by undergoing an epithelial-to-mesenchymal transmission (EMT). Recent work has revealed that cells in intermediate states of EMT acquire an augmented capacity for tumor-cell dissemination. These states have been characterized by molecular markers, but the structural features and the cellular mechanisms that underlie the acquisition of their invasive properties are still unknown. Using human mammary epithelial cells, we generated cells in intermediate states of EMT through the induction of a single EMT-inducing transcription factor, ZEB1, and cells in a mesenchymal state by stimulation with TGFβ. In stereotypic and spatially-defined culture conditions, the architecture, internal organization and mechanical properties of cells in the epithelial, intermediate and mesenchymal state were measured and compared. We found that the lack of intercellular cohesiveness in epithelial and mesenchymal cells can be detected early by microtubule destabilization and the repositioning of the centrosome from the cell-cell junction to the cell center. Consistent with their high migration velocities, cells in intermediate states produced low contractile forces compared with epithelial and mesenchymal cells. The high contractile forces in mesenchymal cells powered a retrograde flow pushing the nucleus away from cell adhesion to the extracellular matrix. Therefore, cells in intermediate state had structural and mechanical properties that were distinct but not necessarily intermediate between epithelial and mesenchymal cells. Based on these observations, we found that a panel of triple-negative breast cancer lines had intermediate rather than mesenchymal characteristics suggesting that the structural and mechanical properties of the intermediate state are important for understanding tumor-cell dissemination.

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Section: The Initiation Of Emt and Establishment Of The Intermediate supporting

confidence: 93%

“…Leal-Egaña et al, 2017). Consistent with the observed levels of cell traction forces (Figure 4c,d) E/M cells migrated faster than E cells, whereas M cells migrated slower(Figure 6e).…”

supporting

confidence: 88%

Section: The Initiation Of Emt and Establishment Of The Intermediate mentioning

confidence: 99%

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Biophysical properties of intermediate states of EMT outperform both epithelial and mesenchymal states

Margaron

Nagai

Guyon

et al. 2019

Preprint

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“…At the level of tissues, they drive the shape changes supporting tissue remodeling such as extension (Rauzi et al, 2008), compaction (Maître et al, 2015) and folding (Hughes et al, 2018). At the level of the cell, they affect shape (Mogilner and Keren, 2009), migration (Leal-Egaña et al, 2017;Maiuri et al, 2015), division (Sedzinski et al, 2011) and differentiation (Kilian et al, 2010;McBeath et al, 2004). Contractile forces are produced mainly by actomyosin bundles or stress fibers in adherent cells (Chrzanowska-Wodnicka and Burridge, 1996;Katoh et al, 1998;Naumanen et al, 2008), and by a cortical meshwork of randomly oriented filaments in poorly-adherent cells (Chugh and Paluch, 2018;Chugh et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Stress fibers are embedded in a contractile cortical network

Vignaud

Copos

Leterrier

et al. 2020

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Contractile actomyosin networks generate intracellular forces essential for the regulation of cell shape, migration, and cell-fate decisions, ultimately leading to the remodeling and patterning of tissues. Although actin filaments aligned in bundles represent the main source of traction-force production in adherent cells, there is increasing evidence that these bundles form interconnected and interconvertible structures with the rest of the intracellular actin network. In this study, we explored how these bundles are connected to the surrounding cortical network and the mechanical impact of these interconnected structures on the production and distribution of traction forces on the extracellular matrix and throughout the cell. By using a combination of hydrogel micropatterning, traction-force microscopy and laser photoablation, we measured the relaxation of the cellular traction field in response to local photoablations at various positions within the cell. Our experimental results and modeling of the mechanical response of the network revealed that bundles were fully embedded along their entire length in a continuous and contractile network of cortical filaments. Moreover, the propagation of the contraction of these bundles throughout the entire cell was dependent on this embedding. In addition, these bundles appeared to originate from the alignment and coalescence of thin and unattached cortical actin filaments from the surrounding mesh.

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“…Moreover, geometry, at the level of a single cell or of the colony, has been shown to have an important effect in the regulation of cell growth [26]. Some studies have demonstrated that genotypically identical cells can adopt different phenotypes according to their environment [27] or tumourigenic factors [28]. Notably, the interplay between spatial position and signalling is critical in development, for example in morphogenesis [29], in cell competition [30] and in cell-fate decision through Notch signalling patterning [31,32].…”

Section: Introductionmentioning

confidence: 99%

PhysiBoSS: a multi-scale agent based modelling framework integrating physical dimension and cell signalling

Letort

Montagud

Stoll

et al. 2018

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Due to the complexity of biological systems, their heterogeneity, and the internal regulation of each cell and its surrounding, mathematical models that take into account cell signalling, cell population behaviour and the extracellular environment are particularly helpful to understand such complex systems. However, very few of these tools, freely available and computationally efficient, are currently available. To fill this gap, we present here our open-source software, PhysiBoSS, which is built on two available software packages that focus on different scales: intracellular signalling using continuous-time markovian Boolean modelling (MaBoSS) and multicellular behaviour using agent-based modelling (PhysiCell).The multi-scale feature of PhysiBoSS -its agent-based structure and the possibility to integrate any Boolean network to it -provide a flexible and computationally efficient framework to study heterogeneous cell population growth in diverse experimental set-ups. This tool allows one to explore the effect of environmental and genetic alterations of individual cells at the population level, bridging the critical gap from genotype to phenotype. PhysiBoSS thus becomes very useful when studying population response to treatment, mutations effects, cell modes of invasion or isomorphic morphogenesis events.To illustrate potential use of PhysiBoSS, we studied heterogeneous cell fate decisions in response to TNF treatment in a 2-D cell population and in a tumour cell 3-D spheroid. We explored the effect of different treatment regimes and the behaviour and selection of several resistant mutants. We highlighted the importance of spatial information on the population dynamics by considering the effect of competition for resources like oxygen. PhysiBoSS is freely available on GitHub (https://github.com/gletort/PhysiBoSS), and is distributed open source under the BSD 3-clause license. It is compatible with most Unix systems, and a Docker package (https://hub.docker.com/r/gletort/physiboss/) is provided to ease its deployment in other systems.

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The size-speed-force relationship governs migratory cell response to tumorigenic factors

Cited by 32 publications

References 86 publications

Biophysical properties of intermediate states of EMT outperform both epithelial and mesenchymal states

Biophysical properties of intermediate states of EMT outperform both epithelial and mesenchymal states

Stress fibers are embedded in a contractile cortical network

PhysiBoSS: a multi-scale agent based modelling framework integrating physical dimension and cell signalling

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