Faculty Opinions recommendation of The role of single cell mechanical behavior and polarity in driving collective cell migration.

Abstract Cell migration plays pivotal roles in many biological processes; however, its underlying mechanism remains unclear. Here, we find that NudC-like protein 2 (NudCL2), a cochaperone of heat shock protein 90 (Hsp90), modulates cell migration by stabilizing both myosin-9 and lissencephaly protein 1 (LIS1). Either knockdown or knockout of NudCL2 significantly increases single-cell migration, but has no significant effect on collective cell migration. Immunoprecipitation–mass spectrometry and western blotting analyses reveal that NudCL2 binds to myosin-9 in mammalian cells. Depletion of NudCL2 not only decreases myosin-9 protein levels, but also results in actin disorganization. Ectopic expression of myosin-9 efficiently reverses defects in actin disorganization and single-cell migration in cells depleted of NudCL2. Interestingly, knockdown of myosin-9 increases both single and collective cell migration. Depletion of LIS1, a NudCL2 client protein, suppresses both single and collective cell migration, which exhibits the opposite effect compared with myosin-9 depletion. Co-depletion of myosin-9 and LIS1 promotes single-cell migration, resembling the phenotype caused by NudCL2 depletion. Furthermore, inhibition of Hsp90 ATPase activity also reduces the Hsp90-interacting protein myosin-9 stability and increases single-cell migration. Forced expression of Hsp90 efficiently reverses myosin-9 protein instability and the defects induced by NudCL2 depletion, but not vice versa. Taken together, these data suggest that NudCL2 plays an important role in the precise regulation of cell migration by stabilizing both myosin-9 and LIS1 via Hsp90 pathway.

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Heterogenous adhesion of follower cells affects tension profile and velocity of leader cells in primary keratocyte collective cell migration

10.1101/2020.12.08.417063 ◽

2020 ◽

Author(s):

Baishali Mukherjee ◽

Madhura Chakraborty ◽

Arikta Biswas ◽

Rajesh Kumble Nayak ◽

Bidisha Sinha

Keyword(s):

Cell Migration ◽

Single Cell ◽

Cell Interactions ◽

Collective Cell Migration ◽

Membrane Tension ◽

High Cell ◽

Cell Sheets ◽

Membrane Fluctuations ◽

High Tension ◽

Cell To Cell Variability

AbstractSingle cell studies demonstrate membrane tension to be a central regulator of lamellipodia-driven motility bringing in front-coherence. During collective cell migration, however, tension mapping or existence of intracellular tension-gradients and the effect of cell-cell interactions have remained unexplored. In this study of membrane fluctuations and fluctuation-tension of migrating primary keratocyte cell-sheets, we first show that some leader cells are followed by followers which remain de-adhered from the substrate while being attached to other cells and thus appear to be “taking a ride”. A subtle yet significant enhanced long-timescale velocity in these leaders indicate increased directionality. Intriguingly, such leaders mostly have front-high tension gradients like single keratocytes, while followers and other leaders usually display front-low membrane tension gradients. The front-high tension gradient and higher membrane tension observed in these leaders, despite the high cell-to-cell variability in membrane tension demonstrate how leader-follower interactions and heterogenous adhesion profiles are key in collective cell migration.

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Unleashing shear: Role of intercellular traction and cellular moments in collective cell migration

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2019.11.048 ◽

2020 ◽

Vol 522 (2) ◽

pp. 279-285

Author(s):

Neel G. Patel ◽

Alyson Nguyen ◽

Ningyong Xu ◽

Shivani Ananthasekar ◽

Diego F. Alvarez ◽

...

Keyword(s):

Cell Migration ◽

Collective Cell Migration

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Collective cell migration in development

The Journal of Cell Biology ◽

10.1083/jcb.201508047 ◽

2016 ◽

Vol 212 (2) ◽

pp. 143-155 ◽

Cited By ~ 187

Author(s):

Elena Scarpa ◽

Roberto Mayor

Keyword(s):

Cell Migration ◽

Cell Adhesion ◽

Collective Cell Migration ◽

Germ Layer ◽

Collective Migration ◽

Developmental Models ◽

Border Cell ◽

Guidance Cues ◽

Tracheal Branching

During embryonic development, tissues undergo major rearrangements that lead to germ layer positioning, patterning, and organ morphogenesis. Often these morphogenetic movements are accomplished by the coordinated and cooperative migration of the constituent cells, referred to as collective cell migration. The molecular and biomechanical mechanisms underlying collective migration of developing tissues have been investigated in a variety of models, including border cell migration, tracheal branching, blood vessel sprouting, and the migration of the lateral line primordium, neural crest cells, or head mesendoderm. Here we review recent advances in understanding collective migration in these developmental models, focusing on the interaction between cells and guidance cues presented by the microenvironment and on the role of cell–cell adhesion in mechanical and behavioral coupling of cells within the collective.

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P-cadherin promotes collective cell migration via a Cdc42-mediated increase in mechanical forces

The Journal of Cell Biology ◽

10.1083/jcb.201505105 ◽

2016 ◽

Vol 212 (2) ◽

pp. 199-217 ◽

Cited By ~ 57

Author(s):

Cédric Plutoni ◽

Elsa Bazellieres ◽

Maïlys Le Borgne-Rochet ◽

Franck Comunale ◽

Agusti Brugues ◽

...

Keyword(s):

Cell Migration ◽

Cell Polarity ◽

Cell Biology ◽

Cell Polarization ◽

Collective Cell Migration ◽

Mechanical Forces ◽

Tumor Aggressiveness ◽

And Migration ◽

Cell Cell

Collective cell migration (CCM) is essential for organism development, wound healing, and metastatic transition, the primary cause of cancer-related death, and it involves cell–cell adhesion molecules of the cadherin family. Increased P-cadherin expression levels are correlated with tumor aggressiveness in carcinoma and aggressive sarcoma; however, how P-cadherin promotes tumor malignancy remains unknown. Here, using integrated cell biology and biophysical approaches, we determined that P-cadherin specifically induces polarization and CCM through an increase in the strength and anisotropy of mechanical forces. We show that this mechanical regulation is mediated by the P-cadherin/β-PIX/Cdc42 axis; P-cadherin specifically activates Cdc42 through β-PIX, which is specifically recruited at cell–cell contacts upon CCM. This mechanism of cell polarization and migration is absent in cells expressing E- or R-cadherin. Thus, we identify a specific role of P-cadherin through β-PIX–mediated Cdc42 activation in the regulation of cell polarity and force anisotropy that drives CCM.

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HAX1 impact on collective cell migration, cell adhesion, and cell shape is linked to the regulation of actomyosin contractility

Molecular Biology of the Cell ◽

10.1091/mbc.e19-05-0304 ◽

2019 ◽

Vol 30 (25) ◽

pp. 3024-3036 ◽

Cited By ~ 3

Author(s):

Anna Balcerak ◽

Alicja Trebinska-Stryjewska ◽

Maciej Wakula ◽

Mateusz Chmielarczyk ◽

Urszula Smietanka ◽

...

Keyword(s):

Breast Cancer ◽

Cell Migration ◽

Single Cell ◽

Cancer Progression ◽

Cancer Cell Line ◽

Cell Junctions ◽

Collective Cell Migration ◽

Actomyosin Contractility ◽

Epithelial Cell Layer ◽

Cell Cell

HAX1 protein is involved in the regulation of apoptosis, cell motility and calcium homeostasis. Its overexpression was reported in several tumors, including breast cancer. This study demonstrates that HAX1 has an impact on collective, but not single-cell migration, thus indicating the importance of cell–cell contacts for the HAX1-mediated effect. Accordingly, it was shown that HAX1 knockdown affects cell–cell junctions, substrate adhesion, and epithelial cell layer integrity. As demonstrated here, these effects can be attributed to the modulation of actomyosin contractility through changes in RhoA and septin signaling. Additionally, it was shown that HAX1 does not influence invasive potential in the breast cancer cell line, suggesting that its role in breast cancer progression may be linked instead to collective invasion of the epithelial cells but not single-cell dissemination.

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