Mechano-sensing and cell migration: a 3D model approach

Borau, Carlos; Kamm, Roger D.; García-Aznar, J.M.

doi:10.1088/1478-3975/8/6/066008

Cited by 61 publications

(63 citation statements)

References 77 publications

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“…The direction of cell movement in these models is calculated from the orientation of the surrounding matrix fibers (24) and the random direction associated with the protrusion forces (21,47). After obtaining the direction of the cell migration, the assumed asymmetric distribution of the receptors at the front and rear edges of the cell, creates a net traction force, which moves the cells within the matrix (21,22).…”

Section: Discussionmentioning

confidence: 99%

Modeling the two-way feedback between contractility and matrix realignment reveals a nonlinear mode of cancer cell invasion

Ahmadzadeh

Webster

Behera

et al. 2017

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

165

151

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Cancer cell invasion from primary tumors is mediated by a complex interplay between cellular adhesions, actomyosin-driven contractility, and the physical characteristics of the extracellular matrix (ECM). Here, we incorporate a mechanochemical free-energy-based approach to elucidate how the two-way feedback loop between cell contractility (induced by the activity of chemomechanical interactions such as Ca 2+ and Rho signaling pathways) and matrix fiber realignment and strain stiffening enables the cells to polarize and develop contractile forces to break free from the tumor spheroids and invade into the ECM. Interestingly, through this computational model, we are able to identify a critical stiffness that is required by the matrix to break intercellular adhesions and initiate cell invasion. Also, by considering the kinetics of the cell movement, our model predicts a biphasic invasiveness with respect to the stiffness of the matrix. These predictions are validated by analyzing the invasion of melanoma cells in collagen matrices of varying concentration. Our model also predicts a positive correlation between the elongated morphology of the invading cells and the alignment of fibers in the matrix, suggesting that cell polarization is directly proportional to the stiffness and alignment of the matrix. In contrast, cells in nonfibrous matrices are found to be rounded and not polarized, underscoring the key role played by the nonlinear mechanics of fibrous matrices. Importantly, our model shows that mechanical principles mediated by the contractility of the cells and the nonlinearity of the ECM behavior play a crucial role in determining the phenotype of the cell invasion.cell invasion | cell contractility | matrix realignment | Rho pathway | fibrous matrices C ell invasion into the surrounding matrix from nonvascularized primary tumors is the main mechanism by which cancer cells migrate to nearby blood vessels and metastasize to eventually form secondary tumors. This process is mediated by an intricate intercoupling between intracellular forces (such as cell contractility) and extracellular forces (adhesions and protrusions) that depend on the stiffness of the surrounding stroma and the alignment of matrix fibers. Previous experimental studies have examined the influence of these forces on the migratory behavior of cells during invasion. For example, the comparison between cell contractility in malignant and normal tissues has shown that the cells with malignant phenotype have a higher level of contractility (1-4). This elevated contractility is directly proportional to factors such as the stiffness of the extracellular matrix (ECM) and the fiber realignment (5-7), suggesting that the cross talk between ECM and intracellular contractility mediated by mechanosensory signaling pathways is also implicated in metastasis. Specifically, the activity of Rho, a myosin GTPase that regulates the activity of myosins, is elevated in proportion to the stiffness of the surrounding matrix (1,8,9), and inhibition of Rho-associated ...

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Section: Discussionmentioning

confidence: 99%

Modeling the two-way feedback between contractility and matrix realignment reveals a nonlinear mode of cancer cell invasion

Ahmadzadeh

Webster

Behera

et al. 2017

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

165

151

View full text Add to dashboard Cite

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“…A recent numerical modeling of cell migration in 3D gel that explicitly took into account cell contractility mechanisms also shows that cells in a uniform gel tend to move towards a constrained boundary. 2 Another numerical simulation provided quantitative understanding of the physical process that cells remodel the surrounding matrix during invasion. 20 These observations lend support to mechanics-based explanation to our findings.…”

Section: Discussionmentioning

confidence: 99%

Effects of Migrating Cell-Induced Matrix Reorganization on 3D Cancer Cell Migration

et al. 2014

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Abstract-The migration of cells is fundamental to a number of physiological/pathological processes, ranging from embryonic development, tissue regeneration to cancer metastasis. Current research on cell migration is largely based on simplified in vitro models that assume a homogeneous microenvironment and overlook the modification of extracellular matrix (ECM) by the cells. To address this shortcoming, we developed a nested threedimensional (3D) collagen hydrogel model mimicking the connective tissue confronted by highly malignant breast cancer cells, MDA-MB-231. Strikingly, our findings revealed two distinct cell migration patterns: a rapid and directionally persistent collective migration of the leader cells and a more randomized migration in the regions that have previously been significantly modified by cells. The cell-induced modifications, which typically include clustering and alignment of fibers, effectively segmented the matrix into smaller sub-regions. Our results suggest that in an elastic 3D matrix, the presence of adjacent cells that have modified the matrix may in fact become physical hurdle to a migrating cell. Furthermore, our study emphasizes the need for a micromechanical understanding in the context of cancer invasion that allows for cell-induced modification of ECM and a heterogeneous cell migration.

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“…(9b) and the law for its time evolution is a delicate issue. In [8], d pol is characterized according to the dynamics of the evolution of the cell cytoskeleton, which reorganizes itself according to its mechanosensing mechanisms. A simplified version of the model proposed in [8], and also adopted in the present work, is represented by the choice…”

Section: Growth Lawsmentioning

confidence: 99%

A poroelastic mixture model of mechanobiological processes in biomass growth: theory and application to tissue engineering

et al. 2017

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In this article we propose a novel mathematical description of biomass growth that combines poroelastic theory of mixtures and cellular population models. The formulation, potentially applicable to general mechanobiological processes, is here used to study the engineered cultivation in bioreactors of articular chondrocytes, a process of Regenerative Medicine characterized by a complex interaction among spatial scales (from nanometers to centimeters), temporal scales (from seconds to weeks) and biophysical phenomena (fluid-controlled nutrient transport, delivery and consumption; mechanical deformation of a multiphase porous medium). The principal contribution of this research is the inclusion of the concept of cellular ''force isotropy'' as one of the main factors influencing cellular activity. In this description, the induced cytoskeletal tensional states trigger signalling transduction cascades regulating functional cell behavior. This mechanims is modeled by a parameter which estimates the influence of local force isotropy by the norm of the deviatoric part of the total stress tensor. According to the value of the estimator, isotropic mechanical conditions are assumed to be the promoting factor of extracellular matrix production whereas anisotropic conditions are assumed to promote cell proliferation. The resulting mathematical formulation is a coupled system of nonlinear partial differential equations comprising: conservation laws for mass and linear momentum of the growing biomass; advection-diffusion-reaction laws for nutrient (oxygen) transport, delivery and consumption; and kinetic laws for cellular population dynamics. To develop a reliable computational tool for the simulation of the engineered tissue growth process the nonlinear differential problem is numerically solved by: (1) temporal semidiscretization; (2) linearization via a fixed-point map; and (3) finite element spatial approximation. The biophysical accuracy of the mechanobiological model is assessed in the analysis of a simplified 1D geometrical setting. Simulation results show that: (1) isotropic/anisotropic conditions are strongly influenced by both maximum cell specific growth rate and mechanical boundary 123Meccanica (2017) 52: 3273-3297 DOI 10.1007/s11012-017-0638-9 conditions enforced at the interface between the biomass construct and the interstitial fluid; (2) experimentally measured features of cultivated articular chondrocytes, such as the early proliferation phase and the delayed extracellular matrix production, are well described by the computed spatial and temporal evolutions of cellular populations.

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Mechano-sensing and cell migration: a 3D model approach

Cited by 61 publications

References 77 publications

Modeling the two-way feedback between contractility and matrix realignment reveals a nonlinear mode of cancer cell invasion

Modeling the two-way feedback between contractility and matrix realignment reveals a nonlinear mode of cancer cell invasion

Effects of Migrating Cell-Induced Matrix Reorganization on 3D Cancer Cell Migration

A poroelastic mixture model of mechanobiological processes in biomass growth: theory and application to tissue engineering

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