Matrix rigidity regulates a switch between TGF-β1–induced apoptosis and epithelial–mesenchymal transition

Leight, Jennifer L.; Wozniak, Michele A.; Chen, Sophia; Lynch, Michelle L.; Chen, Christopher

doi:10.1091/mbc.e11-06-0537

Cited by 388 publications

(369 citation statements)

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“…We test the model for varying ECM stiffness (0.1-1000 kPa) and confinement due to channel widths between 20 and 80 mm, emulating several previous experiments (1)(2)(3)(4)9,13). Consistent with the known ability of cells to actively respond to ECM stiffness (3,4,14), our model predicts that cell clusters scatter more readily on stiffer ECMs. Surprisingly, the cells trapped within 2D islands do not undergo scattering (13) as they do inside 3D channels with vertical walls (9).…”

Section: Introductionmentioning

confidence: 59%

“…Over the years, numerous experimental studies have revealed new phenotypes of mechanosensitive and ECMdependent cell scattering and EMT (1)(2)(3)(4)9,13,19,31,32). However, a clear conceptual framework of how cellular mechanisms of forces and adhesions physically interact with the ECM and enable EMT was missing.…”

Section: Discussionmentioning

confidence: 99%

“…The system of ordinary differential equations (ODEs) developed above (Eqs. 1, 5, and 6), corresponding to CE adhesions a, CC junctions b, cellular adhesion node position x c , and nuclear node position x n , is solved using Runge-Kutta scheme from time t ¼ 0-120 h, consistent with experimental culture period (1)(2)(3)(4)9). As the CE adhesions grow (Eq.…”

Section: Simulation Of Cell Clusters In Defined Ecmsmentioning

confidence: 99%

“…Thus, the physical interaction of individual cells with their ECM can play a crucial role in determining the structural integrity of multicell clusters. Over the years, several studies have established that stiffer ECMs cause greater subcellular forces and protrusions, stronger cell-ECM adhesions, and more polarized morphology of individual cells, which in turn lead to the rupture of cell-cell junctions followed by EMT (1)(2)(3)(4). Since cell polarization is a key precursor to the stiffness-induced cell scattering in these studies, we asked whether the cells trapped inside confined environments could undergo a similar shape polarization, as we and others have shown earlier (5)(6)(7)(8), and commence dissociation from their native cluster.…”

Section: Introductionmentioning

confidence: 99%

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Scattering of Cell Clusters in Confinement

Pathak

2016

Biophysical Journal

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Epithelial-to-mesenchymal transition (EMT) enables scattering of cell clusters and disseminates motile cells to distant locations in vivo during embryonic development and cancer metastasis. Both stiffness and topography of the extracellular matrix (ECM) have been shown to influence EMT. In this work, we examine how the integrity of epithelial cell clusters is regulated by subcellular forces, protrusions, and adhesions for varying ECM inputs, such as stiffness, topography, and dimensionality. Our model simulates multicell networks of defined sizes and shapes in ECMs of varied stiffness and geometry. The integrity of cell clusters is dictated by cell-cell junctions, which depend on subcellular forces and adhesion dynamics within each cell of the cluster. Our simulations demonstrate an enhanced dissociation of cell-cell junctions in stiffer and more confined three-dimensional (3D) environments, consistent with experimental findings. In narrow channels, the cell edges parallel to the axis of channels lose their cell-cell junctions more readily than those oriented in the perpendicular direction. The inhibition of protrusive activity and cell polarity disables confinement-dependent cell scattering. Here, cell adhesion and spreading along channel walls is found to be essential for scattering. The model also predicts that two-dimensional (2D) confinement of clusters restricts cell spreading and simultaneously blunts the confinement-sensitive cell scattering. This new, to our knowledge, multiscale model integrates molecular adhesion dynamics, subcellular forces, cellular deformation, and macroscale mechanical properties of the ECM to predict the state of cell clusters of defined shapes and sizes. The predictions made by our model not only match experimental findings from a number of experimental setups, but also provide a new conceptual framework for understanding mechanosensitive cell scattering and EMT.

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Section: Introductionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Section: Simulation Of Cell Clusters In Defined Ecmsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Scattering of Cell Clusters in Confinement

Pathak

2016

Biophysical Journal

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“…This effect is not mediated by Smad signaling, but by the PI3K/Akt pathway. 133 Matrix stiffness is important in controlling control the strength of AJs in collective migration. 134 The composition of the matrix itself is regulated by the fibroblasts, which can be activated by paracrine factors secreted from the tumor.…”

Section: The Fate Of Cell-cell Adhesion In Tumor Progressionmentioning

confidence: 99%