A minimal mechanics model for mechanosensing of substrate rigidity gradient in durotaxis

Marzban, Bahador; Yi, Xiaosu; Yuan, Hongyan

doi:10.1007/s10237-018-1001-3

Cited by 14 publications

(12 citation statements)

References 38 publications

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“…However, the results obtained from our minimal model sufficiently capture our experimental observations of β AR activation on cellular force generation (Fig 1E), indicating that we are capturing the predominant mechanisms of traction force generation. Moreover, our observations are consistent with previous models of cellular traction force generation with increasing substrate stiffness (45). Taken together, these data from both computational modeling (Fig 2) and experiments (Fig 1E) substantiate that β AR activation increases cellular force generation by increasing the number of active motors per stress fiber and suggest that cells may tune force production through distinct yet complementary mechanisms for soluble versus mechanical cues.…”

Section: Ar Activation Increases Cellular Force Generation By Enhancisupporting

confidence: 91%

β-adrenergic signaling modulates cancer cell mechanotype through a RhoA-ROCK-myosin II axis

Kim

Vazquez-Hidalgo

Abdou

et al. 2019

Preprint

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The ability of cells to deform and generate forces are key mechanical properties that are implicated in metastasis. While various soluble and mechanical cues are known to regulate cancer cell mechanical phenotype or mechanotype, our knowledge of how cells translate external signals into changes in mechanotype is still emerging. We previously discovered that activation of β -adrenergic signaling, which results from soluble stress hormone cues, causes cancer cells to be stiffer or less deformable; this stiffer mechanotype was associated with increased cell motility and invasion. Here, we characterize how β -adrenergic activation is translated into changes in cellular mechanotype by identifying molecular mediators that regulate key components of mechanotype including cellular deformability, traction forces, and nonmuscle myosin II (NMII) activity. Using a micropillar assay and computational modelling, we determine that β AR activation increases cellular force generation by increasing the number of actin-myosin binding events; this mechanism is distinct from how cells increase force production in response to matrix stiffness, suggesting that cells regulate their mechanotype using a complementary mechanism in response to stress hormone cues. To identify the molecules that modulate cellular mechanotype with β AR activation, we use a high throughput filtration platform to screen the effects of pharmacologic and genetic perturbations on β AR regulation of whole cell deformability. Our results indicate that β AR activation decreases cancer cell deformability and increases invasion by signaling through RhoA, ROCK, and NMII. Our findings establish β AR-RhoA-ROCK-NMII as a primary signaling axis that mediates cancer cell mechanotype, which provides a foundation for future interventions to stop metastasis.

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Section: Ar Activation Increases Cellular Force Generation By Enhancisupporting

confidence: 91%

β-adrenergic signaling modulates cancer cell mechanotype through a RhoA-ROCK-myosin II axis

Kim

Vazquez-Hidalgo

Abdou

et al. 2019

Preprint

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“…In addition to polarizing in response to cell-cell forces (Section 2.3.2), cells can also polarize in response to asymmetric forces at the cell-substrate interface [52,78]. In particular, given that cells exert larger tractions on more adhesive and/or stiffer substrates, gradients of substrate adhesivity and/or stiffness can polarize cells [79][80][81]. The ensuing migrations towards regions of higher adhesivity and/or stiffness are known as haptotaxis and durotaxis, respectively.…”

Section: Substrate-induced Polarizationmentioning

confidence: 99%

“…A general feature of cell monolayers-and possibly one that is intuitive to any cell biologist who has ever performed cell cultureis that cells growing on a dish slow down their motion as the cell density increases 80 . From a physical perspective, this behaviour is reminiscent of that of granular materials such as sand or coffee beans close to a jamming transition; as the system density increases, each constitutive element becomes trapped by its neighbours, the energy required for structural rearrangements rises, and the system transitions from a fluid to a disordered solid 81 .…”

Section: Nature Physicsmentioning

confidence: 99%

Physical Models of Collective Cell Migration

Alert

Trepat

2020

Annu. Rev. Condens. Matter Phys.

286

269

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Collective cell migration is a key driver of embryonic development, wound healing, and some types of cancer invasion. Here we provide a physical perspective of the mechanisms underlying collective cell migration. We begin with a catalogue of the cell-cell and cell-substrate interactions that govern cell migration, which we classify into positional and orientational interactions. We then review the physical models that have been developed to explain how these interactions give rise to collective cellular movement. These models span the sub-cellular to the supracellular scales, and they include lattice models, phase fields models, active network models, particle models, and continuum models. For each type of model, we discuss its formulation, its limitations, and the main emergent phenomena that it has successfully explained. These phenomena include flocking and fluid-solid transitions, as well as wetting, fingering, and mechanical waves in spreading epithelial monolayers. We close by outlining remaining challenges and future directions in the physics of collective cell migration.

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“…A simple mechanics model has been presented by us previously to explain how exactly the larger focal adhesion stress is generated at the stiffer region of the substrate. Static equilibrium of the cell adhering to the substrate directly yield the disparate traction stress on regions of different rigidity 58 .…”

Section: Simulation Of Durotaxismentioning

confidence: 99%

In silico mechanobiochemical modeling of morphogenesis in cell monolayers

Marzban

Qing

et al. 2017

Preprint

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Cell morphogenesis is a fundamental process involved in tissue formation. One of the challenges in the fabrication of living tissues in vitro is to recapitulate the complex morphologies of individual cells. Despite tremendous progress in understanding biophysical principles underlying tissue/organ morphogenesis at the organ level, little work has been done to understand morphogenesis at the cellular and microtissue level. In this work, we developed a 2D computational model for studying cell morphogenesis in monolayer tissues. The model is mainly composed of four modules: mechanics of cytoskeleton, cell motility, cell-substrate interaction, and cell-cell interaction. The model integrates the biochemical and mechanical activities within individual cells spatiotemporally. Finite element method (FEM) is used to model the irregular shapes of cells and to solve the resulting system of reaction-diffusion-stress equations. Automated mesh generation is used to handle the element distortion in FEM due to the large shape changes of the cells. The computer program can simulate tens to hundreds of cells interacting with each other and with the elastic substrate on desktop workstations efficiently. The simulations demonstrated that our computational model can be used to study cell polarization, single cell migration, durotaxis, and morphogenesis in cell monolayers.

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A minimal mechanics model for mechanosensing of substrate rigidity gradient in durotaxis

Cited by 14 publications

References 38 publications

β-adrenergic signaling modulates cancer cell mechanotype through a RhoA-ROCK-myosin II axis

β-adrenergic signaling modulates cancer cell mechanotype through a RhoA-ROCK-myosin II axis

Physical Models of Collective Cell Migration

In silico mechanobiochemical modeling of morphogenesis in cell monolayers

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