scholarly journals Proteolipid protein 2 drives collective cell migration via ZO-1 mediated cytoskeletal remodeling at the leading-edge

2021 ◽  
Author(s):  
Dipanjana Ghosh ◽  
Ankita Dutta ◽  
Anjali Kashyap ◽  
Neeraj Upmanyu ◽  
Sunando Datta
Keyword(s):  
Cell Migration ◽  
Cancer Progression ◽  
Transmembrane Protein ◽  
Leading Edge ◽  
Proteolipid Protein ◽  
Vital Role ◽  
Collective Cell Migration ◽  
Cell Integrity ◽  
Cellular Mechanisms ◽  
Cell Dynamics

Collective cell migration (CCM), where cell-cell integrity remained preserved during the movement, plays an important role in the progression of cancer. However, studies describing CCM in cancer progression are majorly focused on the effect of extracellular tissue components on moving cell plasticity. The molecular and cellular mechanisms of CCM during cancer progression remained poorly explored. Here we report that proteolipid protein 2 (PLP2), a colonic epithelium enriched transmembrane protein, plays a vital role in the CCM of invasive colorectal cancer (CRC) epithelium by modulating leading-edge cell dynamics in 2D (two-dimension). The extracellular pool of PLP2, secreted via exosomes was also found to contribute to the event. During CCM, the protein was found to exist in association with ZO-1 and involved in the positioning of the latter at the migrating edge. PLP2 mediated positioning of ZO-1 at the leading-edge further alters actin cytoskeletal organization that involves Rac1 activation. Together our findings demonstrate that PLP2, via its association with ZO-1, drives the collective cell migration in CRC epithelium by modulating leading-edge actin cytoskeleton and thereby opened up new avenues of cancer research.

scholarly journals Biomechanics of Collective Cell Migration in Cancer Progression: Experimental and Computational Methods

2019 ◽  
Vol 5 (8) ◽  
pp. 3766-3787 ◽  
Author(s):  
Catalina-Paula Spatarelu ◽  
Hao Zhang ◽  
Dung Trung Nguyen ◽  
Xinyue Han ◽  
Ruchuan Liu ◽  
...  
Keyword(s):  
Cell Migration ◽  
Computational Methods ◽  
Cancer Progression ◽  
Collective Cell Migration

scholarly journals α4/α9 Integrins Coordinate Epithelial Cell Migration Through Local Suppression of MAP Kinase Signaling Pathways

2021 ◽  
Vol 9 ◽  
Author(s):  
Willow Hight-Warburton ◽  
Robert Felix ◽  
Andrew Burton ◽  
Hannah Maple ◽  
Magda S. Chegkazi ◽  
...  
Keyword(s):  
Cell Migration ◽  
Protein Complexes ◽  
Focal Adhesions ◽  
Leading Edge ◽  
Collective Cell Migration ◽  
Keratinocyte Proliferation ◽  
Basal Keratinocytes ◽  
Keratinocyte Cell

Adhesion of basal keratinocytes to the underlying extracellular matrix (ECM) plays a key role in the control of skin homeostasis and response to injury. Integrin receptors indirectly link the ECM to the cell cytoskeleton through large protein complexes called focal adhesions (FA). FA also function as intracellular biochemical signaling platforms to enable cells to respond to changing extracellular cues. The α4β1 and α9β1 integrins are both expressed in basal keratinocytes, share some common ECM ligands, and have been shown to promote wound healing in vitro and in vivo. However, their roles in maintaining epidermal homeostasis and relative contributions to pathological processes in the skin remain unclear. We found that α4β1 and α9β1 occupied distinct regions in monolayers of a basal keratinocyte cell line (NEB-1). During collective cell migration (CCM), α4 and α9 integrins co-localized along the leading edge. Pharmacological inhibition of α4β1 and α9β1 integrins increased keratinocyte proliferation and induced a dramatic change in cytoskeletal remodeling and FA rearrangement, detrimentally affecting CCM. Further analysis revealed that α4β1/α9β1 integrins suppress extracellular signal-regulated kinase (ERK1/2) activity to control migration through the regulation of downstream kinases including Mitogen and Stress Activated Kinase 1 (MSK1). This work demonstrates the roles of α4β1 and α9β1 in regulating migration in response to damage cues.

scholarly journals Mechanochemical coupling and junctional forces during collective cell migration

2019 ◽  
Author(s):  
J. Bui ◽  
D. E. Conway ◽  
R. L. Heise ◽  
S.H. Weinberg
Keyword(s):  
Cell Migration ◽  
Rho Gtpases ◽  
Cancer Metastasis ◽  
Rho Gtpase ◽  
Critical Role ◽  
Leading Edge ◽  
Collective Cell Migration ◽  
Gtpase Activity ◽  
Modeling Framework ◽  
Cell Cell

ABSTRACTCell migration, a fundamental physiological process in which cells sense and move through their surrounding physical environment, plays a critical role in development and tissue formation, as well as pathological processes, such as cancer metastasis and wound healing. During cell migration, dynamics are governed by the bidirectional interplay between cell-generated mechanical forces and the activity of Rho GTPases, a family of small GTP-binding proteins that regulate actin cytoskeleton assembly and cellular contractility. These interactions are inherently more complex during the collective migration of mechanically coupled cells, due to the additional regulation of cell-cell junctional forces. In this study, we present a minimal modeling framework to simulate the interactions between mechanochemical signaling in individual cells and interactions with cell-cell junctional forces during collective cell migration. We find that migration of individual cells depends on the feedback between mechanical tension and Rho GTPase activity in a biphasic manner. During collective cell migration, waves of Rho GTPase activity mediate mechanical contraction/extension and thus synchronization throughout the tissue. Further, cell-cell junctional forces exhibit distinct spatial patterns during collective cell migration, with larger forces near the leading edge. Larger junctional force magnitudes are associated with faster collective cell migration and larger tissue size. Simulations of heterogeneous tissue migration exhibit a complex dependence on the properties of both leading and trailing cells. Computational predictions demonstrate that collective cell migration depends on both the emergent dynamics and interactions between cellular-level Rho GTPase activity and contractility, and multicellular-level junctional forces.

scholarly journals Fingering instability in spreading epithelial monolayers: roles of cell polarisation, substrate friction and contractile stresses

Soft Matter ◽  
2021 ◽  
Author(s):  
Carolina Trenado ◽  
Luis L. Bonilla ◽  
Alejandro Martínez-Calvo
Keyword(s):  
Wound Healing ◽  
Cell Migration ◽  
Cancer Progression ◽  
Coherent Structures ◽  
Crucial Role ◽  
Collective Cell Migration ◽  
Developmental Processes ◽  
Epithelial Monolayers ◽  
Fingering Instability

Collective cell migration plays a crucial role in many developmental processes that underlie morphogenesis, wound healing, or cancer progression. In such coordinated behaviours, cells are organised in coherent structures and...

scholarly journals Cancer Invasion: Patterns and Mechanisms

Acta Naturae ◽  
2015 ◽  
Vol 7 (2) ◽  
pp. 17-28 ◽  
Author(s):  
N. V. Krakhmal ◽  
M. V. Zavyalova ◽  
E. V. Denisov ◽  
S. V. Vtorushin ◽  
V. M. Perelmuter
Keyword(s):  
Cell Migration ◽  
Tumor Cells ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Cell Invasion ◽  
Cancer Invasion ◽  
Collective Cell Migration ◽  
Cancer Cell Migration ◽  
Cancer Cell Invasion ◽  
Invasion Patterns

Cancer invasion and the ability of malignant tumor cells for directed migration and metastasis have remained a focus of research for many years. Numerous studies have confirmed the existence of two main patterns of cancer cell invasion: collective cell migration and individual cell migration, by which tumor cells overcome barriers of the extracellular matrix and spread into surrounding tissues. Each pattern of cell migration displays specific morphological features and the biochemical/molecular genetic mechanisms underlying cell migration. Two types of migrating tumor cells, mesenchymal (fibroblast-like) and amoeboid, are observed in each pattern of cancer cell invasion. This review describes the key differences between the variants of cancer cell migration, the role of epithelial-mesenchymal, collective-amoeboid, mesenchymal-amoeboid, and amoeboid-mesenchymal transitions, as well as the significance of different tumor factors and stromal molecules in tumor invasion. The data and facts collected are essential to the understanding of how the patterns of cancer cell invasion are related to cancer progression and therapy efficacy. Convincing evidence is provided that morphological manifestations of the invasion patterns are characterized by a variety of tissue (tumor) structures. The results of our own studies are presented to show the association of breast cancer progression with intratumoral morphological heterogeneity, which most likely reflects the types of cancer cell migration and results from different activities of cell adhesion molecules in tumor cells of distinct morphological structures.

scholarly journals Inhibition of epithelial cell migration and Src/FAK signaling by SIRT3

2018 ◽  
Vol 115 (27) ◽  
pp. 7057-7062 ◽  
Author(s):  
Jaewon J. Lee ◽  
Robert A. H. van de Ven ◽  
Elma Zaganjor ◽  
Mei Rosa Ng ◽  
Amey Barakat ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Leading Edge ◽  
Breast Cancers ◽  
Human Breast ◽  
Ros Signaling ◽  
Epithelial Cell Migration ◽  
Sirt3 Expression

Metastasis remains the leading cause of cancer mortality, and reactive oxygen species (ROS) signaling promotes the metastatic cascade. However, the molecular pathways that control ROS signaling relevant to metastasis are little studied. Here, we identify SIRT3, a mitochondrial deacetylase, as a regulator of cell migration via its control of ROS signaling. We find that, although mitochondria are present at the leading edge of migrating cells, SIRT3 expression is down-regulated during migration, resulting in elevated ROS levels. This SIRT3-mediated control of ROS represses Src oxidation and attenuates focal adhesion kinase (FAK) activation. SIRT3 overexpression inhibits migration and metastasis in breast cancer cells. Finally, in human breast cancers, SIRT3 expression is inversely correlated with metastatic outcome and Src/FAK signaling. Our results reveal a role for SIRT3 in cell migration, with important implications for breast cancer progression.

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

2019 ◽  
Vol 30 (25) ◽  
pp. 3024-3036 ◽  
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.

scholarly journals Spatial confinement of receptor activity by tyrosine phosphatase during directional cell migration

2020 ◽  
Vol 117 (25) ◽  
pp. 14270-14279
Author(s):  
Zhiwen Zhu ◽  
Yongping Chai ◽  
Huifang Hu ◽  
Wei Li ◽  
Wen-Jun Li ◽  
...  
Keyword(s):  
Cell Migration ◽  
Actin Polymerization ◽  
Transmembrane Protein ◽  
Tyrosine Phosphatase ◽  
Leading Edge ◽  
Receptor Activity ◽  
Actin Assembly ◽  
Neuroblast Migration ◽  
Directional Cell Migration ◽  
Migrating Cells

Directional cell migration involves signaling cascades that stimulate actin assembly at the leading edge, and additional pathways must inhibit actin polymerization at the rear. During neuroblast migration inCaenorhabditis elegans, the transmembrane protein MIG-13/Lrp12 acts through the Arp2/3 nucleation-promoting factors WAVE and WASP to guide the anterior migration. Here we show that a tyrosine kinase, SRC-1, directly phosphorylates MIG-13 and promotes its activity on actin assembly at the leading edge. In GFP knockin animals, SRC-1 and MIG-13 distribute along the entire plasma membrane of migrating cells. We reveal that a receptor-like tyrosine phosphatase, PTP-3, maintains the F-actin polarity during neuroblast migration. Recombinant PTP-3 dephosphorylates SRC-1–dependent MIG-13 phosphorylation in vitro. Importantly, the endogenous PTP-3 accumulates at the rear of the migrating neuroblast, and its extracellular domain is essential for directional cell migration. We provide evidence that the asymmetrically localized tyrosine phosphatase PTP-3 spatially restricts MIG-13/Lrp12 receptor activity in migrating cells.

scholarly journals Collective cell migration without proliferation: density determines cell velocity and wave velocity

2018 ◽  
Vol 5 (5) ◽  
pp. 172421 ◽  
Author(s):  
Sham Tlili ◽  
Estelle Gauquelin ◽  
Brigitte Li ◽  
Olivier Cardoso ◽  
Benoît Ladoux ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cell Density ◽  
Wave Velocity ◽  
Cell Monolayer ◽  
Leading Edge ◽  
Collective Cell Migration ◽  
Tumour Metastasis ◽  
Long Duration ◽  
Cell Velocity ◽  
Moving Front

Collective cell migration contributes to embryogenesis, wound healing and tumour metastasis. Cell monolayer migration experiments help in understanding what determines the movement of cells far from the leading edge. Inhibiting cell proliferation limits cell density increase and prevents jamming; we observe long-duration migration and quantify space–time characteristics of the velocity profile over large length scales and time scales. Velocity waves propagate backwards and their frequency depends only on cell density at the moving front. Both cell average velocity and wave velocity increase linearly with the cell effective radius regardless of the distance to the front. Inhibiting lamellipodia decreases cell velocity while waves either disappear or have a lower frequency. Our model combines conservation laws, monolayer mechanical properties and a phenomenological coupling between strain and polarity: advancing cells pull on their followers, which then become polarized. With reasonable values of parameters, this model agrees with several of our experimental observations. Together, our experiments and model disantangle the respective contributions of active velocity and of proliferation in monolayer migration, explain how cells maintain their polarity far from the moving front, and highlight the importance of strain–polarity coupling and density in long-range information propagation.

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