scholarly journals Cellular crowd control: overriding endogenous cell coordination makes cell migration more susceptible to external programming

2021 ◽  
Author(s):  
Gawoon Shim ◽  
Danelle Devenport ◽  
Daniel J. Cohen
Keyword(s):  
Cell Migration ◽  
Cell Adhesion ◽  
Mouse Skin ◽  
Cellular Systems ◽  
Cell Junctions ◽  
External Control ◽  
Collective Behaviors ◽  
Primary Mouse ◽  
E Cadherin ◽  
Cell Cell

AbstractAs collective cell migration is essential in biological processes spanning development, healing, and cancer progression, methods to externally program cell migration are of great value. However, problems can arise if the external commands compete with strong, pre-existing collective behaviors in the tissue or system. We investigate this problem by applying a potent external migratory cue—electrical stimulation and electrotaxis—to primary mouse skin monolayers where we can tune cell-cell adhesion strength to modulate endogenous collectivity. Monolayers with high cell-cell adhesion showed strong natural coordination and resisted electrotactic control, with this conflict actively damaging the leading edge of the tissue. However, reducing pre-existing coordination in the tissue by specifically inhibiting E-cadherin-dependent cell-cell adhesion, either by disrupting the formation of cell-cell junctions with E-cadherin specific antibodies or rapidly dismantling E-cadherin junctions with calcium chelators, significantly improved controllability. Finally, we applied this paradigm of weakening existing coordination to improve control to demonstrate accelerated wound closure in vitro. These results are in keeping with those from diverse, non-cellular systems, and confirm that endogenous collectivity should be considered as a key, quantitative design variable when optimizing external control of collective migration.

scholarly journals Overriding native cell coordination enhances external programming of collective cell migration

2021 ◽  
Vol 118 (29) ◽  
pp. e2101352118
Author(s):  
Gawoon Shim ◽  
Danelle Devenport ◽  
Daniel J. Cohen
Keyword(s):  
Cell Migration ◽  
Cell Adhesion ◽  
Mouse Skin ◽  
Cell Junctions ◽  
External Control ◽  
Collective Cell Migration ◽  
Collective Behaviors ◽  
Primary Mouse ◽  
E Cadherin ◽  
Cell Cell

As collective cell migration is essential in biological processes spanning development, healing, and cancer progression, methods to externally program cell migration are of great value. However, problems can arise if the external commands compete with strong, preexisting collective behaviors in the tissue or system. We investigate this problem by applying a potent external migratory cue—electrical stimulation and electrotaxis—to primary mouse skin monolayers where we can tune cell–cell adhesion strength to modulate endogenous collectivity. Monolayers with high cell–cell adhesion showed strong natural coordination and resisted electrotactic control, with this conflict actively damaging the leading edge of the tissue. However, reducing preexisting coordination in the tissue by specifically inhibiting E-cadherin–dependent cell–cell adhesion, either by disrupting the formation of cell–cell junctions with E-cadherin–specific antibodies or rapidly dismantling E-cadherin junctions with calcium chelators, significantly improved controllability. Finally, we applied this paradigm of weakening existing coordination to improve control and demonstrate accelerated wound closure in vitro. These results are in keeping with those from diverse, noncellular systems and confirm that endogenous collectivity should be considered as a key quantitative design variable when optimizing external control of collective migration.

Cdx1 or Cdx2 expression activates E-cadherin-mediated cell-cell adhesion and compaction in human COLO 205 cells

2004 ◽  
Vol 287 (1) ◽  
pp. G104-G114 ◽  
Author(s):  
Matthew S. Keller ◽  
Toshihiko Ezaki ◽  
Rong-Jun Guo ◽  
John P. Lynch
Keyword(s):  
Gene Expression ◽  
Cell Adhesion ◽  
Gene Expression Pattern ◽  
Cell Junctions ◽  
Specific Gene ◽  
Specific Response ◽  
Specific Gene Expression ◽  
Cdx2 Expression ◽  
E Cadherin ◽  
Cell Cell

A mature columnar intestinal epithelium develops late in embryogenesis and is maintained throughout the life of the organism. Although the mechanisms driving intestine-specific gene expression have been well studied, those promoting the acquisition of cell-cell junctions, columnar morphogenesis, and polarization have been less studied. The Cdx homeodomain transcription factors (Cdx1 and Cdx2) regulate intestine-specific gene expression and intestinal epithelial differentiation. We report here that Cdx expression induces E-cadherin activity and cell-cell adhesion in human COLO 205 cancer cells. Within days of Cdx1 or Cdx2 expression, a new homotypic cell-cell adhesion phenotype is induced. This is a specific response to Cdx, inasmuch as a Cdx1 mutant failed to elicit the effect. Additionally, Cdx-expressing COLO 205 cells demonstrate a reduced proliferative capacity and an increase in the mRNA expression of differentiation-associated genes. Electron micrographs of these cells demonstrate induction of tight, adherens, and desmosomal junctions, as well as a columnar shape and apical microvilli. Investigations of the adhesion phenotype determined that it was Ca2+dependent and could be blocked by an E-cadherin-blocking antibody. However, E-cadherin protein levels and intracellular distribution were unchanged. Cdx expression restored the ability of the cell membranes to adhere and undergo compaction. We conclude that Cdx1 or Cdx2 expression is sufficient to induce an E-cadherin-dependent adhesion of COLO 205 cells. This adhesion is associated with polarization and cell-cell membrane compaction, as well as induction of a differentiated gene-expression pattern. Ascertaining the mechanism for this novel Cdx effect may yield insight into the development of mature colonic epithelium.

scholarly journals Actin protrusions push on E-cadherin to maintain epithelial cell-cell adhesion

2019 ◽  
Author(s):  
John Xiao He Li ◽  
Vivian W. Tang ◽  
William M. Brieher
Keyword(s):  
Cell Adhesion ◽  
Actin Polymerization ◽  
Mdck Cells ◽  
Myosin Ii ◽  
Cell Junctions ◽  
Apical Junctions ◽  
Actin Protrusions ◽  
Adhesive Contacts ◽  
E Cadherin ◽  
Cell Cell

AbstractCadherin mediated cell-cell adhesion is actin dependent, but the precise role of actin in maintaining cell-cell adhesion is not fully understood. Actin polymerization-dependent protrusive activity is required to push distally separated cells close enough together to initiate contact. Whether protrusive activity is required to maintain adhesion in confluent sheets of epithelial cells is not known. By electron microscopy as well as live cell imaging, we have identified a population of protruding actin microspikes that operate continuously near apical junctions of polarized MDCK cells. Live imaging shows that microspikes containing E-cadherin extend into gaps between E-cadherin clusters on neighboring cells while reformation of cadherin clusters across the cell-cell boundary triggers microspike withdrawal. We identify Arp2/3, EVL, and CRMP-1 as three actin assembly factors necessary for microspike formation. Depleting these factors from cells using RNAi results in myosin II-dependent unzipping of cadherin adhesive bonds. Therefore, actin polymerization-dependent protrusive activity operates continuously at cadherin cell-cell junctions to keep them shut and to prevent myosin II-dependent contractility from tearing cadherin adhesive contacts apart.

scholarly journals Keratin 19 maintains E-cadherin localization at the cell surface and stabilizes cell-cell adhesion of MCF7 cells

2020 ◽  
Author(s):  
Sarah Alsharif ◽  
Pooja Sharma ◽  
Karina Bursch ◽  
Rachel Milliken ◽  
Meagan Collins ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cell Adhesion ◽  
Cell Mechanics ◽  
Mcf7 Cells ◽  
Growth And Survival ◽  
Recycling Endosomes ◽  
Keratin 19 ◽  
E Cadherin ◽  
Cell Cell

AbstractA cytoskeletal protein keratin 19 (K19) is highly expressed in breast cancer but its effects on breast cancer cell mechanics are unclear. Using KRT19 knockout (KO) cells and cells where K19 expression was rescued, we found that K19 is required to maintain rounded epithelial-like shape and tight cell-cell adhesion of MCF7 cells. A loss of K19 resulted in a lower level of plakoglobin and internalization of E-cadherin in early and recycling endosomes. Inhibiting internalization restored cell-cell adhesion of KRT19 KO cells, suggesting E-cadherin internalization contributes to defective adhesion. Ultimately, while K19 inhibited cell migration, it was required for cells to form colonies in suspension. Our results suggest that K19 stabilizes E-cadherin complexes at the cell membrane to maintain cell-cell adhesion which inhibits cell migration but provides growth and survival advantages for circulating tumor cells. These findings provide context-dependent roles of K19 during metastasis.

scholarly journals Formin-mediated actin polymerization at cell–cell junctions stabilizes E-cadherin and maintains monolayer integrity during wound repair

2016 ◽  
Vol 27 (18) ◽  
pp. 2844-2856 ◽  
Author(s):  
Megha Vaman Rao ◽  
Ronen Zaidel-Bar
Keyword(s):  
Cell Adhesion ◽  
Wound Repair ◽  
Actin Polymerization ◽  
Cell Junctions ◽  
Epithelial Tissue ◽  
Collective Cell Migration ◽  
Epithelial Junctions ◽  
Major Factors ◽  
E Cadherin ◽  
Cell Cell

Cadherin-mediated cell–cell adhesion is required for epithelial tissue integrity in homeostasis, during development, and in tissue repair. E-cadherin stability depends on F-actin, but the mechanisms regulating actin polymerization at cell–cell junctions remain poorly understood. Here we investigated a role for formin-mediated actin polymerization at cell–cell junctions. We identify mDia1 and Fmnl3 as major factors enhancing actin polymerization and stabilizing E-cadherin at epithelial junctions. Fmnl3 localizes to adherens junctions downstream of Src and Cdc42 and its depletion leads to a reduction in F-actin and E-cadherin at junctions and a weakening of cell–cell adhesion. Of importance, Fmnl3 expression is up-regulated and junctional localization increases during collective cell migration. Depletion of Fmnl3 or mDia1 in migrating monolayers results in dissociation of leader cells and impaired wound repair. In summary, our results show that formin activity at epithelial cell–cell junctions is important for adhesion and the maintenance of epithelial cohesion during dynamic processes, such as wound repair.

scholarly journals WAVE2 Protein Complex Coupled to Membrane and Microtubules

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Kazuhide Takahashi
Keyword(s):  
Cell Migration ◽  
Cell Adhesion ◽  
Cancer Cell ◽  
Migration And Invasion ◽  
Cancer Cell Migration ◽  
Actin Assembly ◽  
Cell Migration And Invasion ◽  
Directional Cell Migration ◽  
E Cadherin ◽  
Cell Cell

E-cadherin is one of the key molecules in the formation of cell-cell adhesion and interacts intracellularly with a group of proteins collectively named catenins, through which the E-cadherin-catenin complex is anchored to actin-based cytoskeletal components. Although cell-cell adhesion is often disrupted in cancer cells by either genetic or epigenetic alterations in cell adhesion molecules, disruption of cell-cell adhesion alone seems to be insufficient for the induction of cancer cell migration and invasion. A small GTP-binding protein, Rac1, induces the specific cellular protrusions lamellipodia via WAVE2, a member of WASP/WAVE family of the actin cytoskeletal regulatory proteins. Biochemical and pharmacological investigations have revealed that WAVE2 interacts with many proteins that regulate microtubule growth, actin assembly, and membrane targeting of proteins, all of which are necessary for directional cell migration through lamellipodia formation. These findings might have important implications for the development of effective therapeutic agents against cancer cell migration and invasion.

scholarly journals Actin protrusions push at apical junctions to maintain E-cadherin adhesion

2019 ◽  
Vol 117 (1) ◽  
pp. 432-438 ◽  
Author(s):  
John Xiao He Li ◽  
Vivian W. Tang ◽  
William M. Brieher
Keyword(s):  
Cell Adhesion ◽  
Actin Polymerization ◽  
Mdck Cells ◽  
Myosin Ii ◽  
Cell Junctions ◽  
Apical Junctions ◽  
Actin Protrusions ◽  
Adhesive Contacts ◽  
E Cadherin ◽  
Cell Cell

Cadherin-mediated cell–cell adhesion is actin-dependent, but the precise role of actin in maintaining cell–cell adhesion is not fully understood. Actin polymerization-dependent protrusive activity is required to push distally separated cells close enough to initiate contact. Whether protrusive activity is required to maintain adhesion in confluent sheets of epithelial cells is not known. By electron microscopy as well as live cell imaging, we have identified a population of protruding actin microspikes that operate continuously near apical junctions of polarized Madin-Darby canine kidney (MDCK) cells. Live imaging shows that microspikes containing E-cadherin extend into gaps between E-cadherin clusters on neighboring cells, while reformation of cadherin clusters across the cell–cell boundary correlates with microspike withdrawal. We identify Arp2/3, EVL, and CRMP-1 as 3 actin assembly factors necessary for microspike formation. Depleting these factors from cells using RNA interference (RNAi) results in myosin II-dependent unzipping of cadherin adhesive bonds. Therefore, actin polymerization-dependent protrusive activity operates continuously at cadherin cell–cell junctions to keep them shut and to prevent myosin II-dependent contractility from tearing cadherin adhesive contacts apart.

scholarly journals DDR1 triggers epithelial cell differentiation by promoting cell adhesion through stabilization of E-cadherin

2011 ◽  
Vol 22 (7) ◽  
pp. 940-953 ◽  
Author(s):  
Yi-Chun Yeh ◽  
Chia-Ching Wu ◽  
Yang-Kao Wang ◽  
Ming-Jer Tang
Keyword(s):  
Cell Adhesion ◽  
Underlying Mechanism ◽  
Dominant Negative ◽  
Cell Junctions ◽  
Dominant Negative Mutant ◽  
Protein Levels ◽  
Epithelial Plasticity ◽  
The Stability ◽  
E Cadherin ◽  
Cell Cell

Discoidin domain receptor 1 (DDR1) promotes E-cadherin–mediated adhesion. The underlying mechanism and its significance, however, have not been elucidated. Here we show that DDR1 overexpression augmented, whereas dominant negative mutant (DN-DDR1) or knockdown of DDR1 inhibited E-cadherin localized in cell-cell junctions in epithelial cells. DDR1 changed the localization and abundance of E-cadherin, as well as epithelial plasticity, as manifested by enhancement of microvilli formation and alteration of cytoskeletal organization. DDR1 also reduced protein abundance of mesenchymal markers, whereas DN-DDR1 and sh-DDR1 showed opposite effects. These results suggest that expression of DDR1 increases epithelial plasticity. Expression of DDR1 augmented E-cadherin protein levels by decreasing its degradation rate. Photobleaching and photoconversion of E-cadherin conjugated with Eos fluorescence protein demonstrated that DDR1 increased the stability of E-cadherin on the cell membrane, whereas sh-DDR1 decreased it. Pull-down assay and expression of constitutively active or dominant-negative Cdc42 showed that DDR1 stabilized E-cadherin through inactivation of Cdc42. Altogether, our results show that DDR1 promotes cell-cell adhesion and differentiation through stabilization of E-cadherin, which is mediated by Cdc42 inactivation.

scholarly journals Cancer Cell Invasion in Three-dimensional Collagen Is Regulated Differentially by Gα13 Protein and Discoidin Domain Receptor 1-Par3 Protein Signaling

2015 ◽  
Vol 291 (4) ◽  
pp. 1605-1618 ◽  
Author(s):  
Christina R. Chow ◽  
Kazumi Ebine ◽  
Lawrence M. Knab ◽  
David J. Bentrem ◽  
Krishan Kumar ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Cell Invasion ◽  
Single Cells ◽  
Three Dimensional ◽  
Cell Junctions ◽  
Membrane Type ◽  
Discoidin Domain Receptor 1 ◽  
E Cadherin ◽  
Cell Cell

Cancer cells can invade in three-dimensional collagen as single cells or as a cohesive group of cells that require coordination of cell-cell junctions and the actin cytoskeleton. To examine the role of Gα13, a G12 family heterotrimeric G protein, in regulating cellular invasion in three-dimensional collagen, we established a novel method to track cell invasion by membrane type 1 matrix metalloproteinase-expressing cancer cells. We show that knockdown of Gα13 decreased membrane type 1 matrix metalloproteinase-driven proteolytic invasion in three-dimensional collagen and enhanced E-cadherin-mediated cell-cell adhesion. E-cadherin knockdown reversed Gα13 siRNA-induced cell-cell adhesion but failed to reverse the effect of Gα13 siRNA on proteolytic invasion. Instead, concurrent knockdown of E-cadherin and Gα13 led to an increased number of single cells rather than groups of cells. Significantly, knockdown of discoidin domain receptor 1 (DDR1), a collagen-binding protein that also co-localizes to cell-cell junctions, reversed the effects of Gα13 knockdown on cell-cell adhesion and proteolytic invasion in three-dimensional collagen. Knockdown of the polarity protein Par3, which can function downstream of DDR1, also reversed the effects of Gα13 knockdown on cell-cell adhesion and proteolytic invasion in three-dimensional collagen. Overall, we show that Gα13 and DDR1-Par3 differentially regulate cell-cell junctions and the actin cytoskeleton to mediate invasion in three-dimensional collagen.

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