Matrix compliance regulates Rac1b localization, NADPH oxidase assembly, and epithelial–mesenchymal transition

Lee, Kang Ae; Chen, Qike K.; Lui, Cecillia; Cichon, Magdalena A.; Radisky, Derek C.; Nelson, Celeste M.

doi:10.1091/mbc.e12-02-0166

Cited by 95 publications

(135 citation statements)

References 74 publications

(78 reference statements)

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“…The model also accounts for stiffness and geometry of the ECM surrounding the multicell network. 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.…”

Section: Introductionmentioning

confidence: 56%

“…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%

See 3 more Smart Citations

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: 56%

Section: Discussionmentioning

confidence: 99%

Section: Simulation Of Cell Clusters In Defined Ecmsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Scattering of Cell Clusters in Confinement

Pathak

2016

Biophysical Journal

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“…The mechanical properties of the microenvironment, as well as active mechanical influences, for example mechanical strains and stresses, regulate a range of basic cellular phenomena, including cell proliferation, apoptosis, epithelial-to-mesenchymal transition and stem cell fate decisions (Chen et al, 1997;Gilbert et al, 2010;Lee et al, 2012;. Importantly, different organs (Engler et al, 2006) and even separate tissue components within the same organ (Lopez et al, 2011) are characterized by distinct mechanical properties, and this mechanical modularity may serve to pattern cellular behaviors, giving rise to the regional differences that ultimately drive morphogenesis.…”

Section: D Spatial and Temporal Patterning Of Mechanicsmentioning

confidence: 99%

Bioengineering approaches to guide stem cell-based organogenesis

2014

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During organogenesis, various molecular and physical signals are orchestrated in space and time to sculpt multiple cell types into functional tissues and organs. The complex and dynamic nature of the process has hindered studies aimed at delineating morphogenetic mechanisms in vivo, particularly in mammals. Recent demonstrations of stem cell-driven tissue assembly in culture offer a powerful new tool for modeling and dissecting organogenesis. However, despite the highly organotypic nature of stem cell-derived tissues, substantial differences set them apart from their in vivo counterparts, probably owing to the altered microenvironment in which they reside and the lack of mesenchymal influences. Advances in the biomaterials and microtechnology fields have, for example, afforded a high degree of spatiotemporal control over the cellular microenvironment, making it possible to interrogate the effects of individual microenvironmental components in a modular fashion and rapidly identify organ-specific synthetic culture models. Hence, bioengineering approaches promise to bridge the gap between stem cell-driven tissue formation in culture and morphogenesis in vivo, offering mechanistic insight into organogenesis and unveiling powerful new models for drug discovery, as well as strategies for tissue regeneration in the clinic. We draw on several examples of stem cellderived organoids to illustrate how bioengineering can contribute to tissue formation ex vivo. We also discuss the challenges that lie ahead and potential ways to overcome them.

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Ultrasound‐Induced Mechanical Compaction in Acoustically Responsive Scaffolds Promotes Spatiotemporally Modulated Signaling in Triple Negative Breast Cancer

Humphries

Aliabouzar

Quesada

et al. 2022

Adv Healthcare Materials

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Cancer cells continually sense and respond to mechanical cues from the extracellular matrix (ECM). Interaction with the ECM can alter intracellular signaling cascades, leading to changes in processes that promote cancer cell growth, migration, and survival. The present study used a recently developed composite hydrogel composed of a fibrin matrix and phase‐shift emulsion, termed an acoustically responsive scaffold (ARS), to investigate effects of local mechanical properties on breast cancer cell signaling. Treatment of ARSs with focused ultrasound drives acoustic droplet vaporization (ADV) in a spatiotemporally controlled manner, inducing local compaction and stiffening of the fibrin matrix adjacent to the matrix–bubble interface. Combining ARSs and live single cell imaging of triple‐negative breast cancer cells, it is discovered that both basal and growth‐factor stimulated activities of protein kinase B (also known as Akt) and extracellular signal‐regulated kinase (ERK), two major kinases driving cancer progression, negatively correlate with increasing distance from the ADV‐induced bubble both in vitro and in a mouse model. Together, these data demonstrate that local changes in ECM compaction regulate Akt and ERK signaling in breast cancer and support further applications of the novel ARS technology to analyze spatial and temporal effects of ECM mechanics on cell signaling and cancer biology.

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Matrix compliance regulates Rac1b localization, NADPH oxidase assembly, and epithelial–mesenchymal transition

Cited by 95 publications

References 74 publications

Scattering of Cell Clusters in Confinement

Scattering of Cell Clusters in Confinement

Bioengineering approaches to guide stem cell-based organogenesis

Ultrasound‐Induced Mechanical Compaction in Acoustically Responsive Scaffolds Promotes Spatiotemporally Modulated Signaling in Triple Negative Breast Cancer

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