scholarly journals Senescent stroma induces nuclear deformations in cancer cells via the inhibition of RhoA/ROCK/myosin II-based cytoskeletal tension

2021 ◽  
Author(s):  
Ivie Aifuwa ◽  
Jude M Phillip ◽  
Byoung Kim ◽  
Teresa Luperchio ◽  
Angela Jimenez ◽  
...  
Keyword(s):  
Morphological Changes ◽  
Myosin Ii ◽  
Nuclear Lamina ◽  
Quantitative Microscopy ◽  
Cortical Tension ◽  
Particle Tracking Microrheology ◽  
Mechanical Compliance ◽  
Cytoskeletal Tension ◽  
Secretory Phenotype ◽  
Malignant Transformations

The presence of senescent cells within tissues has been functionally linked to malignant transformations. Here, using tension-gauge tethers technology, particle-tracking microrheology, and quantitative microscopy, we demonstrate that senescent associated secretory phenotype (SASP) derived from senescent fibroblasts impose nuclear lobulations and volume shrinkage on malignant cells, which stems from the loss of RhoA/ROCK/myosin II-based cortical tension. This loss in cytoskeletal tension induces decreased cellular contractility, adhesion, and increased mechanical compliance. These SASP-induced morphological changes are in part mediated by lamin A/C. These findings suggest that SASP induces a defective outside-in mechanotransduction, from actomyosin fibers in the cytoplasm to the nuclear lamina, thereby triggering a cascade of biophysical and biomolecular changes in cells that associate with malignant transformations.

scholarly journals Pharmacological activation of myosin II paralogs to correct cell mechanics defects

2015 ◽  
Vol 112 (5) ◽  
pp. 1428-1433 ◽  
Author(s):  
Alexandra Surcel ◽  
Win Pin Ng ◽  
Hoku West-Foyle ◽  
Qingfeng Zhu ◽  
Yixin Ren ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Mechanics ◽  
Myosin Ii ◽  
Target Space ◽  
Power Stroke ◽  
Invasion And Migration ◽  
Cortical Tension ◽  
Pancreatic Cancer Cells ◽  
Tumor Cell Behavior ◽  
And Migration

Current approaches to cancer treatment focus on targeting signal transduction pathways. Here, we develop an alternative system for targeting cell mechanics for the discovery of novel therapeutics. We designed a live-cell, high-throughput chemical screen to identify mechanical modulators. We characterized 4-hydroxyacetophenone (4-HAP), which enhances the cortical localization of the mechanoenzyme myosin II, independent of myosin heavy-chain phosphorylation, thus increasing cellular cortical tension. To shift cell mechanics, 4-HAP requires myosin II, including its full power stroke, specifically activating human myosin IIB (MYH10) and human myosin IIC (MYH14), but not human myosin IIA (MYH9). We further demonstrated that invasive pancreatic cancer cells are more deformable than normal pancreatic ductal epithelial cells, a mechanical profile that was partially corrected with 4-HAP, which also decreased the invasion and migration of these cancer cells. Overall, 4-HAP modifies nonmuscle myosin II-based cell mechanics across phylogeny and disease states and provides proof of concept that cell mechanics offer a rich drug target space, allowing for possible corrective modulation of tumor cell behavior.

scholarly journals Lipid Players of Cellular Senescence

Metabolites ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 339
Author(s):  
Alec Millner ◽  
G. Ekin Atilla-Gokcumen
Keyword(s):  
Cellular Senescence ◽  
Morphological Changes ◽  
Surrounding Tissue ◽  
Membrane Remodeling ◽  
Protein Targets ◽  
Current State ◽  
New Findings ◽  
Secretory Phenotype ◽  
And Function ◽  
Inflammatory Phenotypes

Lipids are emerging as key players of senescence. Here, we review the exciting new findings on the diverse roles of lipids in cellular senescence, most of which are enabled by the advancements in omics approaches. Senescence is a cellular process in which the cell undergoes growth arrest while retaining metabolic activity. At the organismal level, senescence contributes to organismal aging and has been linked to numerous diseases. Current research has documented that senescent cells exhibit global alterations in lipid composition, leading to extensive morphological changes through membrane remodeling. Moreover, senescent cells adopt a secretory phenotype, releasing various components to their environment that can affect the surrounding tissue and induce an inflammatory response. All of these changes are membrane and, thus, lipid related. Our work, and that of others, has revealed that fatty acids, sphingolipids, and glycerolipids are involved in the initiation and maintenance of senescence and its associated inflammatory components. These studies opened up an exciting frontier to investigate the deeper mechanistic understanding of the regulation and function of these lipids in senescence. In this review, we will provide a comprehensive snapshot of the current state of the field and share our enthusiasm for the prospect of potential lipid-related protein targets for small-molecule therapy in pathologies involving senescence and its related inflammatory phenotypes.

scholarly journals Apoptotic Membrane Blebbing Is Regulated by Myosin Light Chain Phosphorylation

1998 ◽  
Vol 140 (3) ◽  
pp. 627-636 ◽  
Author(s):  
Jason C. Mills ◽  
Nicole L. Stone ◽  
Joseph Erhardt ◽  
Randall N. Pittman
Keyword(s):  
Light Chain ◽  
Myosin Light Chain ◽  
Kinase Inhibitors ◽  
Morphological Changes ◽  
Myosin Ii ◽  
Model System ◽  
Membrane Blebbing ◽  
Execution Phase ◽  
Fragmentation Mechanisms ◽  
Mlc Phosphorylation

The evolutionarily conserved execution phase of apoptosis is defined by characteristic changes occurring during the final stages of death; specifically cell shrinkage, dynamic membrane blebbing, condensation of chromatin, and DNA fragmentation. Mechanisms underlying these hallmark features of apoptosis have previously been elusive, largely because the execution phase is a rapid event whose onset is asynchronous across a population of cells. In the present study, a model system is described for using the caspase inhibitor, z-VAD-FMK, to block apoptosis and generate a synchronous population of cells actively extruding and retracting membrane blebs. This model system allowed us to determine signaling mechanisms underlying this characteristic feature of apoptosis. A screen of kinase inhibitors performed on synchronized blebbing cells indicated that only myosin light chain kinase (MLCK) inhibitors decreased blebbing. Immunoprecipitation of myosin II demonstrated that myosin regulatory light chain (MLC) phosphorylation was increased in blebbing cells and that MLC phosphorylation was prevented by inhibitors of MLCK. MLC phosphorylation is also mediated by the small G protein, Rho. C3 transferase inhibited apoptotic membrane blebbing, supporting a role for a Rho family member in this process. Finally, blebbing was also inhibited by disruption of the actin cytoskeleton. Based on these results, a working model is proposed for how actin/myosin II interactions cause cell contraction and membrane blebbing. Our results provide the first evidence that MLC phosphorylation is critical for apoptotic membrane blebbing and also implicate Rho signaling in these active morphological changes. The model system described here should facilitate future studies of MLCK, Rho, and other signal transduction pathways activated during the execution phase of apoptosis.

scholarly journals Differential basal-to-apical accessibility of lamin A/C epitopes in the nuclear lamina regulated by changes in cytoskeletal tension

2015 ◽  
Vol 14 (12) ◽  
pp. 1252-1261 ◽  
Author(s):  
Teemu O. Ihalainen ◽  
Lina Aires ◽  
Florian A. Herzog ◽  
Ruth Schwartlander ◽  
Jens Moeller ◽  
...  
Keyword(s):  
Nuclear Lamina ◽  
Lamin A ◽  
Cytoskeletal Tension

scholarly journals Cytokinesis in vertebrate cells initiates by contraction of an equatorial actomyosin network composed of randomly oriented filaments

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Felix Spira ◽  
Sara Cuylen-Haering ◽  
Shalin Mehta ◽  
Matthias Samwer ◽  
Anne Reversat ◽  
...  
Keyword(s):  
Myosin Ii ◽  
Local Network ◽  
Polarization Microscopy ◽  
Cleavage Furrow ◽  
Mechanical Forces ◽  
Biological Processes ◽  
Actin Network ◽  
Animal Cells ◽  
Mechanical Tension ◽  
Cortical Tension

The actomyosin ring generates force to ingress the cytokinetic cleavage furrow in animal cells, yet its filament organization and the mechanism of contractility is not well understood. We quantified actin filament order in human cells using fluorescence polarization microscopy and found that cleavage furrow ingression initiates by contraction of an equatorial actin network with randomly oriented filaments. The network subsequently gradually reoriented actin filaments along the cell equator. This strictly depended on myosin II activity, suggesting local network reorganization by mechanical forces. Cortical laser microsurgery revealed that during cytokinesis progression, mechanical tension increased substantially along the direction of the cell equator, while the network contracted laterally along the pole-to-pole axis without a detectable increase in tension. Our data suggest that an asymmetric increase in cortical tension promotes filament reorientation along the cytokinetic cleavage furrow, which might have implications for diverse other biological processes involving actomyosin rings.

scholarly journals The interplay of stiffness and force anisotropies drives embryo elongation

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Thanh Thi Kim Vuong-Brender ◽  
Martine Ben Amar ◽  
Julien Pontabry ◽  
Michel Labouesse
Keyword(s):  
Experimental Data ◽  
Material Properties ◽  
Myosin Ii ◽  
Mechanical Forces ◽  
Cell Behaviour ◽  
Cortical Tension ◽  
Actin Cortex ◽  
Stiffness Anisotropy ◽  
Spatiotemporal Changes ◽  
Tissue Material

The morphogenesis of tissues, like the deformation of an object, results from the interplay between their material properties and the mechanical forces exerted on them. The importance of mechanical forces in influencing cell behaviour is widely recognized, whereas the importance of tissue material properties, in particular stiffness, has received much less attention. Using Caenorhabditis elegans as a model, we examine how both aspects contribute to embryonic elongation. Measuring the opening shape of the epidermal actin cortex after laser nano-ablation, we assess the spatiotemporal changes of actomyosin-dependent force and stiffness along the antero-posterior and dorso-ventral axis. Experimental data and analytical modelling show that myosin-II-dependent force anisotropy within the lateral epidermis, and stiffness anisotropy within the fiber-reinforced dorso-ventral epidermis are critical in driving embryonic elongation. Together, our results establish a quantitative link between cortical tension, material properties and morphogenesis of an entire embryo.

scholarly journals Patterned cortical tension mediated by N-cadherin controls cell geometric order in the Drosophila eye

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Eunice HoYee Chan ◽  
Pruthvi Chavadimane Shivakumar ◽  
Raphaël Clément ◽  
Edith Laugier ◽  
Pierre-François Lenne
Keyword(s):  
Adhesion Molecules ◽  
Myosin Ii ◽  
Control Cell ◽  
Cortical Tension ◽  
Indirect Control ◽  
Drosophila Eye ◽  
Cell Patterns ◽  
Cell Shapes ◽  
Contractile Forces

Adhesion molecules hold cells together but also couple cell membranes to a contractile actomyosin network, which limits the expansion of cell contacts. Despite their fundamental role in tissue morphogenesis and tissue homeostasis, how adhesion molecules control cell shapes and cell patterns in tissues remains unclear. Here we address this question in vivo using the Drosophila eye. We show that cone cell shapes depend little on adhesion bonds and mostly on contractile forces. However, N-cadherin has an indirect control on cell shape. At homotypic contacts, junctional N-cadherin bonds downregulate Myosin-II contractility. At heterotypic contacts with E-cadherin, unbound N-cadherin induces an asymmetric accumulation of Myosin-II, which leads to a highly contractile cell interface. Such differential regulation of contractility is essential for morphogenesis as loss of N-cadherin disrupts cell rearrangements. Our results establish a quantitative link between adhesion and contractility and reveal an unprecedented role of N-cadherin on cell shapes and cell arrangements.

Genetic and morphological evidence for two parallel pathways of cell-cycle-coupled cytokinesis inDictyostelium

2002 ◽  
Vol 115 (10) ◽  
pp. 2241-2251 ◽  
Author(s):  
Akira Nagasaki ◽  
Eugenio L. de Hostos ◽  
Taro Q. P. Uyeda
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Morphological Changes ◽  
Mutant Cell ◽  
Myosin Ii ◽  
Morphological Evidence ◽  
Cleavage Furrow ◽  
Cycle Progression ◽  
Parallel Pathways ◽  
Substrate Adhesion

Myosin-II-null cells of Dictyostelium discoideum cannot divide in suspension, consistent with the dogma that myosin II drives constriction of the cleavage furrow and, consequently, cytokinesis (cytokinesis A). Nonetheless, when grown on substrates, these cells exhibit efficient,cell-cycle-coupled division, suggesting that they possess a novel,myosin-II-independent, adhesion-dependent method of cytokinesis (cytokinesis B). Here we show that double mutants lacking myosin II and either AmiA or coronin, both of which are implicated in cytokinesis B, are incapable of cell-cycle-coupled cytokinesis. These double mutants multiplied mainly by cytokinesis C, a third, inefficient, method of cell division, which requires substrate adhesion and is independent of cell cycle progression. In contrast,double mutants lacking AmiA and coronin were no sicker than each of the single mutants, indicating that the severe defects of myosin II-/AmiA- or myosin II-/coronin-mutants are not simple additive effects of two mutations. We take this as genetic evidence for two parallel pathways both of which lead to cell-cycle-coupled cytokinesis. This conclusion is supported by differences in morphological changes during cytokinesis in the mutant cell lines.

A mechanical function of myosin II in cell motility

1995 ◽  
Vol 108 (1) ◽  
pp. 387-393 ◽  
Author(s):  
P.Y. Jay ◽  
P.A. Pham ◽  
S.A. Wong ◽  
E.L. Elson
Keyword(s):  
Cell Shape ◽  
Myosin Ii ◽  
Mechanical Function ◽  
Null Mutant ◽  
Wild Type ◽  
Cytoskeletal Network ◽  
Cytoskeletal Tension ◽  
Tractional Forces ◽  
Contractile Forces ◽  
Mutant Cells

Myosin II mutant Dictyostelium amoebae crawl more slowly than wild-type cells. Thus, myosin II must contribute to amoeboid locomotion. We propose that contractile forces generated by myosin II help the cell's rear edge to detach from the substratum and retract, allowing the cell to continue forward. To test this hypothesis, we measured the speed of wild-type and myosin II null mutant Dictyostelium cells on surfaces of varying adhesivity. As substratum adhesivity increased, the speed of myosin II null mutant cells decreased substantially compared to wild-type cells, suggesting that the mutant is less able to retract from sticky surfaces. Furthermore, interference reflection microscopy revealed a myosin-II-dependent contraction in wild-type but not null mutant cells that is consistent with a balance of adhesive and contractile forces in retraction. Although myosin II null mutant cells have a defect in retraction, pseudopod extension does not cause the cells to become elongated on sticky surfaces. This suggests a mechanism, based possibly on cytoskeletal tension, for regulating cell shape in locomotion. The tension would result from the transmission of tractional forces through the cytoskeletal network, providing the myosin II null mutant with a limited means of retraction and cell division on a surface.

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