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Qin, Lei, Dazhi Yang, Weihong Yi, Huiling Cao i Guozhi Xiao. "Roles of leader and follower cells in collective cell migration". Molecular Biology of the Cell 32, nr 14 (1.07.2021): 1267–72. http://dx.doi.org/10.1091/mbc.e20-10-0681.
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Collective cell migration is a widely observed phenomenon during animal development, tissue repair, and cancer metastasis. Considering its broad involvement in biological processes, it is essential to understand the basics behind the collective movement. Based on the topology of migrating populations, tissue-scale kinetics, called the “leader–follower” model, has been proposed for persistent directional collective movement. Extensive in vivo and in vitro studies reveal the characteristics of leader cells, as well as the special mechanisms leader cells employ for maintaining their positions in collective migration. However, follower cells have attracted increasing attention recently due to their important contributions to collective movement. In this Perspective, the current understanding of the molecular mechanisms behind the “leader–follower” model is reviewed with a special focus on the force transmission and diverse roles of leaders and followers during collective cell movement.
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Khalil, Antoine A., i Peter Friedl. "Determinants of leader cells in collective cell migration". Integrative Biology 2, nr 11-12 (2010): 568. http://dx.doi.org/10.1039/c0ib00052c.
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Xin, Zhuohan, Keiko Deguchi, Shin-ichiro Suye i Satoshi Fujita. "Quantitative Analysis of Collective Migration by Single-Cell Tracking Aimed at Understanding Cancer Metastasis". International Journal of Molecular Sciences 23, nr 20 (15.10.2022): 12372. http://dx.doi.org/10.3390/ijms232012372.
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Metastasis is a major complication of cancer treatments. Studies of the migratory behavior of cells are needed to investigate and control metastasis. Metastasis is based on the epithelial–mesenchymal transition, in which epithelial cells acquire mesenchymal properties and the ability to leave the population to invade other regions of the body. In collective migration, highly migratory “leader” cells are found at the front of the cell population, as well as cells that “follow” these leader cells. However, the interactions between these cells are not well understood. We examined the migration properties of leader–follower cells during collective migration at the single-cell level. Different mixed ratios of “leader” and “follower” cell populations were compared. Collective migration was quantitatively analyzed from two perspectives: cell migration within the colony and migration of the entire colony. Analysis of the effect of the cell mixing ratio on migration behavior showed that a small number of highly migratory cells enhanced some of the migratory properties of other cells. The results provide useful insights into the cellular interactions in collective cell migration of cancer cell invasion.
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Cao, Yanyang, Priscilla Y. Hwang, Maria Clarke, Jose Almeida, Amit Pathak i Gregory D. Longmore. "Abstract 2423: A Cdh3 - Lam332 signaling axis by a unique subset of leader cells controls breast tumor organoid protrusion dynamics and directed collective migration". Cancer Research 82, nr 12_Supplement (15.06.2022): 2423. http://dx.doi.org/10.1158/1538-7445.am2022-2423.
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Abstract Carcinoma dissemination can occur when heterogeneous tumor and tumor stromal cells clusters migrate together via collective migration. Cells at the front lead and direct collective migration, yet how these leader cells form and interact with the microenvironment to direct migration are not fully appreciated. From live videos of primary mouse and human breast tumor organoids in a 3D microfluidic system that mimics the native breast tumor microenvironment, we developed 3D computational models. These hypothesize that for leader cells to polarize to the leading edge and lead directed collective migration they need to generate high protrusive forces and overcome extracellular matrix (ECM) resistance. From scRNAseq of migrating primary tumor organoids, we identify significant K14+ “leader” cell heterogeneity that differs depending upon the environmental signal. We isolate a unique Cadherin-3 (Cdh3) positive leader cell subpopulation that is necessary and sufficient to lead collective migration. Cdh3 controls leader cell protrusion dynamics through controlling the local production of Laminin-332 which is required for integrin/focal adhesion function. Loss of Cdh3 expression in mouse and human primary breast tumor organoids and invasive breast tumor cell lines significantly impairs directed collective migration. In the absence of leader cell Cdh-Cdh3 intercellular adhesions there is reduced cellular β-catenin levels and Laminin 332 production. In syngeneic, orthotopic transplant mouse models, Cdh3 depletion in tumor cells resulted in decreased laminin 332 production at the invasive edge of primary tumors and decreased lung metastasis. Chromatin Immunoprecipitation experiments revealed that in contacted cells β-catenin and TCF4 are present on Lam α3, β3, and γ2 promoter regions. Laminin 332 production by leader cells was required for optimal Integrin/FA function and cellular protrusion stability. These results indicated that in leader cells local Cdh3-Cdh3/β-catenin regulated Laminin 332 production controls protrusion dynamics and overcomes resistance to ECM to lead directed collective tumor migration. Our findings highlight how a unique subset of leader cells in breast tumors interact with the microenvironment to direct collective migration. Citation Format: Yanyang Cao, Priscilla Y. Hwang, Maria Clarke, Jose Almeida, Amit Pathak, Gregory D. Longmore. A Cdh3 - Lam332 signaling axis by a unique subset of leader cells controls breast tumor organoid protrusion dynamics and directed collective migration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2423.
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Theveneau, Eric, i Claudia Linker. "Leaders in collective migration: are front cells really endowed with a particular set of skills?" F1000Research 6 (27.10.2017): 1899. http://dx.doi.org/10.12688/f1000research.11889.1.
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Collective cell migration is the coordinated movement emerging from the interaction of at least two cells. In multicellular organisms, collective cell migration is ubiquitous. During development, embryonic cells often travel in numbers, whereas in adults, epithelial cells close wounds collectively. There is often a division of labour and two categories of cells have been proposed: leaders and followers. These two terms imply that followers are subordinated to leaders whose proposed broad range of actions significantly biases the direction of the group of cells towards a specific target. These two terms are also tied to topology. Leaders are at the front while followers are located behind them. Here, we review recent work on some of the main experimental models for collective cell migration, concluding that leader-follower terminology may not be the most appropriate. It appears that not all collectively migrating groups are driven by cells located at the front. Moreover, the qualities that define leaders (pathfinding, traction forces and matrix remodelling) are not specific to front cells. These observations indicate that the terms leaders and followers are not suited to every case. We think that it would be more accurate to dissociate the function of a cell from its position in the group. The position of cells can be precisely defined with respect to the direction of movement by purely topological terms such as “front” or “rear” cells. In addition, we propose the more ample and strictly functional definition of “steering cells” which are able to determine the directionality of movement for the entire group. In this context, a leader cell represents only a specific case in which a steering cell is positioned at the front of the group.
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De Pascalis, Chiara, Carlos Pérez-González, Shailaja Seetharaman, Batiste Boëda, Benoit Vianay, Mithila Burute, Cécile Leduc, Nicolas Borghi, Xavier Trepat i Sandrine Etienne-Manneville. "Intermediate filaments control collective migration by restricting traction forces and sustaining cell–cell contacts". Journal of Cell Biology 217, nr 9 (6.07.2018): 3031–44. http://dx.doi.org/10.1083/jcb.201801162.
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Mesenchymal cell migration relies on the coordinated regulation of the actin and microtubule networks that participate in polarized cell protrusion, adhesion, and contraction. During collective migration, most of the traction forces are generated by the acto-myosin network linked to focal adhesions at the front of leader cells, which transmit these pulling forces to the followers. Here, using an in vitro wound healing assay to induce polarization and collective directed migration of primary astrocytes, we show that the intermediate filament (IF) network composed of vimentin, glial fibrillary acidic protein, and nestin contributes to directed collective movement by controlling the distribution of forces in the migrating cell monolayer. Together with the cytoskeletal linker plectin, these IFs control the organization and dynamics of the acto-myosin network, promoting the actin-driven treadmilling of adherens junctions, thereby facilitating the polarization of leader cells. Independently of their effect on adherens junctions, IFs influence the dynamics and localization of focal adhesions and limit their mechanical coupling to the acto-myosin network. We thus conclude that IFs promote collective directed migration in astrocytes by restricting the generation of traction forces to the front of leader cells, preventing aberrant tractions in the followers, and by contributing to the maintenance of lateral cell–cell interactions.
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Caruso, Alexa, Neelakshi Kar i Jeremy Logue. "Abstract B021: Piezo1 and ROCK2 promote fast amoeboid migration in confined environments". Cancer Research 83, nr 2_Supplement_2 (15.01.2023): B021. http://dx.doi.org/10.1158/1538-7445.metastasis22-b021.
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Abstract Cell migration through confined environments may induce a phenotypic transition to fast amoeboid (leader bleb-based) migration. However, the molecular mechanism(s) controlling this phenotypic transition remain poorly understood. Here, we show that regulation of intracellular calcium levels by the plasma membrane tension sensor, Piezo1, promotes the Leader Bleb-Based Migration (LBBM) of melanoma cells. Using a ratiometric assay, intracellular calcium is shown to rise with increasing levels of confinement. Chelation of extracellular and intracellular calcium by BAPTA and BAPTA-AM, respectively, inhibits LBBM. Moreover, in highly motile cells, we found intracellular calcium levels to be dramatically increased at the cell rear. Using the Piezo1 inhibitor, GsMTx4, and RNAi, we can inhibit the phenotypic transition to fast amoeboid (leader bleb-based) migration. Therefore, we wondered if Piezo1 through calcium/calmodulin activates Myosin Light Chain Kinase (MLCK) to promote actomyosin contractility and amoeboid migration. Using a microchannel based assay, we find that ROCK2 and not MLCK, promotes amoeboid migration. Altogether, our work reveals an unanticipated collaboration between Piezo1 and ROCK2 in amoeboid migrating melanoma cells. Citation Format: Alexa Caruso, Neelakshi Kar, Jeremy Logue. Piezo1 and ROCK2 promote fast amoeboid migration in confined environments [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B021.
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Vosatka, Karl W., Sandrine B. Lavenus i Jeremy S. Logue. "A novel Fiji/ImageJ plugin for the rapid analysis of blebbing cells". PLOS ONE 17, nr 4 (29.04.2022): e0267740. http://dx.doi.org/10.1371/journal.pone.0267740.
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When confined, cells have recently been shown to undergo a phenotypic switch to what has been termed, fast amoeboid (leader bleb-based) migration. However, as this is a nascent area of research, few tools are available for the rapid analysis of cell behavior. Here, we demonstrate that a novel Fiji/ImageJ-based plugin, Analyze_Blebs, can be used to quickly obtain cell migration parameters and morphometrics from time lapse images. As validation, we show that Analyze_Blebs can detect significant differences in cell migration and morphometrics, such as the largest bleb size, upon introducing different live markers of F-actin, including F-tractin and LifeAct tagged with green and red fluorescent proteins. We also demonstrate, using flow cytometry, that live markers increase total levels of F-actin. Furthermore, that F-tractin increases cell stiffness, which was found to correlate with a decrease in migration, thus reaffirming the importance of cell mechanics as a determinant of Leader Bleb-Based Migration (LBBM).
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Richardson, Jo, Anton Gauert, Luis Briones Montecinos, Lucía Fanlo, Zainalabdeen Mohmammed Alhashem, Rodrigo Assar, Elisa Marti, Alexandre Kabla, Steffen Härtel i Claudia Linker. "Leader Cells Define Directionality of Trunk, but Not Cranial, Neural Crest Cell Migration". Cell Reports 15, nr 9 (maj 2016): 2076–88. http://dx.doi.org/10.1016/j.celrep.2016.04.067.
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Wynn, Michelle L., Paul M. Kulesa i Santiago Schnell. "Computational modelling of cell chain migration reveals mechanisms that sustain follow-the-leader behaviour". Journal of The Royal Society Interface 9, nr 72 (4.01.2012): 1576–88. http://dx.doi.org/10.1098/rsif.2011.0726.
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Follow-the-leader chain migration is a striking cell migratory behaviour observed during vertebrate development, adult neurogenesis and cancer metastasis. Although cell–cell contact and extracellular matrix (ECM) cues have been proposed to promote this phenomenon, mechanisms that underlie chain migration persistence remain unclear. Here, we developed a quantitative agent-based modelling framework to test mechanistic hypotheses of chain migration persistence. We defined chain migration and its persistence based on evidence from the highly migratory neural crest model system, where cells within a chain extend and retract filopodia in short-lived cell contacts and move together as a collective. In our agent-based simulations, we began with a set of agents arranged as a chain and systematically probed the influence of model parameters to identify factors critical to the maintenance of the chain migration pattern. We discovered that chain migration persistence requires a high degree of directional bias in both lead and follower cells towards the target. Chain migration persistence was also promoted when lead cells maintained cell contact with followers, but not vice-versa. Finally, providing a path of least resistance in the ECM was not sufficient alone to drive chain persistence. Our results indicate that chain migration persistence depends on the interplay of directional cell movement and biased cell–cell contact.
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Park, Song-Yi, Hwanseok Jang, Seon-Young Kim, Dasarang Kim, Yongdoo Park i Sun-Ho Kee. "Expression of E-Cadherin in Epithelial Cancer Cells Increases Cell Motility and Directionality through the Localization of ZO-1 during Collective Cell Migration". Bioengineering 8, nr 5 (11.05.2021): 65. http://dx.doi.org/10.3390/bioengineering8050065.
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Collective cell migration of epithelial tumor cells is one of the important factors for elucidating cancer metastasis and developing novel drugs for cancer treatment. Especially, new roles of E-cadherin in cancer migration and metastasis, beyond the epithelial–mesenchymal transition, have recently been unveiled. Here, we quantitatively examined cell motility using micropatterned free edge migration model with E-cadherin re-expressing EC96 cells derived from adenocarcinoma gastric (AGS) cell line. EC96 cells showed increased migration features such as the expansion of cell islands and straightforward movement compared to AGS cells. The function of tight junction proteins known to E-cadherin expression were evaluated for cell migration by knockdown using sh-RNA. Cell migration and straight movement of EC96 cells were reduced by knockdown of ZO-1 and claudin-7, to a lesser degree. Analysis of the migratory activity of boundary cells and inner cells shows that EC96 cell migration was primarily conducted by boundary cells, similar to leader cells in collective migration. Immunofluorescence analysis showed that tight junctions (TJs) of EC96 cells might play important roles in intracellular communication among boundary cells. ZO-1 is localized to the base of protruding lamellipodia and cell contact sites at the rear of cells, indicating that ZO-1 might be important for the interaction between traction and tensile forces. Overall, dynamic regulation of E-cadherin expression and localization by interaction with ZO-1 protein is one of the targets for elucidating the mechanism of collective migration of cancer metastasis.
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Chapnick, Douglas A., i Xuedong Liu. "Leader cell positioning drives wound-directed collective migration in TGFβ-stimulated epithelial sheets". Molecular Biology of the Cell 25, nr 10 (15.05.2014): 1586–93. http://dx.doi.org/10.1091/mbc.e14-01-0697.
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During wound healing and cancer metastasis, cells are frequently observed to migrate in collective groups. This mode of migration relies on the cooperative guidance of leader and follower cells throughout the collective group. The upstream determinants and molecular mechanisms behind such cellular guidance remain poorly understood. We use live-cell imaging to track the behavior of epithelial sheets of keratinocytes in response to transforming growth factor β (TGFβ), which stimulates collective migration primarily through extracellular regulated kinase 1/2 (Erk1/2) activation. TGFβ-treated sheets display a spatial pattern of Erk1/2 activation in which the highest levels of Erk1/2 activity are concentrated toward the leading edge of a sheet. We show that Erk1/2 activity is modulated by cellular density and that this functional relationship drives the formation of patterns of Erk1/2 activity throughout sheets. In addition, we determine that a spatially constrained pattern of Erk1/2 activity results in collective migration that is primarily wound directed. Conversely, global elevation of Erk1/2 throughout sheets leads to stochastically directed collective migration throughout sheets. Our study highlights how the spatial patterning of leader cells (cells with elevated Erk1/2 activity) can influence the guidance of a collective group of cells during wound healing.
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Reffay, M., M. C. Parrini, O. Cochet-Escartin, B. Ladoux, A. Buguin, S. Coscoy, F. Amblard, J. Camonis i P. Silberzan. "Interplay of RhoA and mechanical forces in collective cell migration driven by leader cells". Nature Cell Biology 16, nr 3 (23.02.2014): 217–23. http://dx.doi.org/10.1038/ncb2917.
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Saénz-de-Santa-María, Inés, Lucía Celada i María-Dolores Chiara. "The Leader Position of Mesenchymal Cells Expressing N-Cadherin in the Collective Migration of Epithelial Cancer". Cells 9, nr 3 (16.03.2020): 731. http://dx.doi.org/10.3390/cells9030731.
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Understanding how heterogeneous cancer cell populations migrate collectively is of paramount importance to arrest metastasis. Here, we applied 3D culture-based approaches for in vitro modeling of the collective migration of squamous carcinoma cells and examine the impact of epithelial and mesenchymal cell interactions on this type of migration. We show that both mesenchymal N-cadherin-expressing cancer cells and cancer-associated fibroblasts cooperate in collective migration of epithelial cancer cells by leading their collective migration. This was consistent with the observed distribution of E-cadherin/N-cadherin in the human carcinoma tissues of head and neck. The presence of “leader” mesenchymal cancer cells or “leader” fibroblasts was significantly associated with metastasis development, recurrent disease and low overall disease survival in head and neck squamous cell carcinomas (HNSCC). In silico analysis of independent public datasets revealed that increased N-cadherin expression in the heterogeneous cancer tissues is associated with disease progression not only in HNSCC but also in other prevalent tumors, such as colorectal, breast and lung cancer. Collectively, our data highlight the importance of mesenchymal cells in collective cell migration and disease progression, findings that may have a broad significance in cancer, especially in those in which aberrant N-cadherin expression negatively impacts disease survival.
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OTGON, Baasansuren, Mun Kit LAI, Ganbat DANAA i Toshiro OHASHI. "Identification of Leader Cells in Migration Using Deep Learning". Proceedings of the JSME Conference on Frontiers in Bioengineering 2020.31 (2020): 1A19. http://dx.doi.org/10.1299/jsmebiofro.2020.31.1a19.
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Basta, Morgan D., A. Sue Menko i Janice L. Walker. "PI3K Isoform-Specific Regulation of Leader and Follower Cell Function for Collective Migration and Proliferation in Response to Injury". Cells 11, nr 21 (7.11.2022): 3515. http://dx.doi.org/10.3390/cells11213515.
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To ensure proper wound healing it is important to elucidate the signaling cues that coordinate leader and follower cell behavior to promote collective migration and proliferation for wound healing in response to injury. Using an ex vivo post-cataract surgery wound healing model we investigated the role of class I phosphatidylinositol-3-kinase (PI3K) isoforms in this process. Our findings revealed a specific role for p110α signaling independent of Akt for promoting the collective migration and proliferation of the epithelium for wound closure. In addition, we found an important role for p110α signaling in orchestrating proper polarized cytoskeletal organization within both leader and wounded epithelial follower cells to coordinate their function for wound healing. p110α was necessary to signal the formation and persistence of vimentin rich-lamellipodia extensions by leader cells and the reorganization of actomyosin into stress fibers along the basal domains of the wounded lens epithelial follower cells for movement. Together, our study reveals a critical role for p110α in the collective migration of an epithelium in response to wounding.
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Reay, M., M. C. Parrini, O. Cochet-Escartin, B. Ladoux, A. Buguin, S. Coscoy, F. Amblard, J. Camonis i P. Silberzan. "Erratum: Interplay of RhoA and mechanical forces in collective cell migration driven by leader cells". Nature Cell Biology 16, nr 4 (kwiecień 2014): 382. http://dx.doi.org/10.1038/ncb2946.
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Vishwakarma, Medhavi, Joachim P. Spatz i Tamal Das. "Mechanobiology of leader–follower dynamics in epithelial cell migration". Current Opinion in Cell Biology 66 (październik 2020): 97–103. http://dx.doi.org/10.1016/j.ceb.2020.05.007.
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Vishwakarma, Medhavi, Basil Thurakkal, Joachim P. Spatz i Tamal Das. "Dynamic heterogeneity influences the leader–follower dynamics during epithelial wound closure". Philosophical Transactions of the Royal Society B: Biological Sciences 375, nr 1807 (27.07.2020): 20190391. http://dx.doi.org/10.1098/rstb.2019.0391.
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Cells of epithelial tissue proliferate and pack together to attain an eventual density homeostasis. As the cell density increases, spatial distribution of velocity and force show striking similarity to the dynamic heterogeneity observed elsewhere in dense granular matter. While the physical nature of this heterogeneity is somewhat known in the epithelial cell monolayer, its biological relevance and precise connection to cell density remain elusive. Relevantly, we had demonstrated how large-scale dynamic heterogeneity in the monolayer stress field in the bulk could critically influence the emergence of leader cells at the wound margin during wound closure, but did not connect the observation to the corresponding cell density. In fact, numerous previous reports had essentially associated long-range force and velocity correlation with either cell density or dynamic heterogeneity, without any generalization. Here, we attempted to unify these two parameters under a single framework and explored their consequence on the dynamics of leader cells, which eventually affected the efficacy of collective migration and wound closure. To this end, we first quantified the dynamic heterogeneity by the peak height of four-point susceptibility. Remarkably, this quantity showed a linear relationship with cell density over many experimental samples. We then varied the heterogeneity, by changing cell density, and found this change altered the number of leader cells at the wound margin. At low heterogeneity, wound closure was slower, with decreased persistence, reduced coordination and disruptive leader–follower interactions. Finally, microscopic characterization of cell–substrate adhesions illustrated how heterogeneity influenced orientations of focal adhesions, affecting coordinated cell movements. Together, these results demonstrate the importance of dynamic heterogeneity in epithelial wound healing. This article is part of the theme issue ‘Multi-scale analysis and modelling of collective migration in biological systems'.
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Lee, Rachel M., Haicen Yue, Wouter-Jan Rappel i Wolfgang Losert. "Inferring single-cell behaviour from large-scale epithelial sheet migration patterns". Journal of The Royal Society Interface 14, nr 130 (maj 2017): 20170147. http://dx.doi.org/10.1098/rsif.2017.0147.
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Cell migration plays an important role in a wide variety of biological processes and can incorporate both individual cell motion and collective behaviour. The emergent properties of collective migration are receiving increasing attention as collective motion's role in diseases such as metastatic cancer becomes clear. Yet, how individual cell behaviour influences large-scale, multi-cell collective motion remains unclear. In this study, we provide insight into the mechanisms behind collective migration by studying cell migration in a spreading monolayer of epithelial MCF10A cells. We quantify migration using particle image velocimetry and find that cell groups have features of motion that span multiple length scales. Comparing our experimental results to a model of collective cell migration, we find that cell migration within the monolayer can be affected in qualitatively different ways by cell motion at the boundary, yet it is not necessary to introduce leader cells at the boundary or specify other large-scale features to recapitulate this large-scale phenotype in simulations. Instead, in our model, collective motion can be enhanced by increasing the overall activity of the cells or by giving the cells a stronger coupling between their motion and polarity. This suggests that investigating the activity and polarity persistence of individual cells will add insight into the collective migration phenotypes observed during development and disease.
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Kabla, Alexandre J. "Collective cell migration: leadership, invasion and segregation". Journal of The Royal Society Interface 9, nr 77 (25.07.2012): 3268–78. http://dx.doi.org/10.1098/rsif.2012.0448.
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A number of biological processes, such as embryo development, cancer metastasis or wound healing, rely on cells moving in concert. The mechanisms leading to the emergence of coordinated motion remain however largely unexplored. Although biomolecular signalling is known to be involved in most occurrences of collective migration, the role of physical and mechanical interactions has only been recently investigated. In this study, a versatile framework for cell motility is implemented in silico in order to study the minimal requirements for the coordination of a group of epithelial cells. We find that cell motility and cell–cell mechanical interactions are sufficient to generate a broad array of behaviours commonly observed in vitro and in vivo . Cell streaming, sheet migration and susceptibility to leader cells are examples of behaviours spontaneously emerging from these simple assumptions, which might explain why collective effects are so ubiquitous in nature. The size of the population and its confinement appear, in particular, to play an important role in the coordination process. In all cases, the complex response of the population can be predicted from the knowledge of the correlation length of the velocity field measured in the bulk of the epithelial layer. This analysis provides also new insights into cancer metastasis and cell sorting, suggesting, in particular, that collective invasion might result from an emerging coordination in a system where single cells are mechanically unable to invade.
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Khalil, Antoine A., i Johan de Rooij. "Cadherin mechanotransduction in leader-follower cell specification during collective migration". Experimental Cell Research 376, nr 1 (marzec 2019): 86–91. http://dx.doi.org/10.1016/j.yexcr.2019.01.006.
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Wynn, Michelle L., Paul Rupp, Paul A. Trainor, Santiago Schnell i Paul M. Kulesa. "Follow-the-leader cell migration requires biased cell–cell contact and local microenvironmental signals". Physical Biology 10, nr 3 (4.06.2013): 035003. http://dx.doi.org/10.1088/1478-3975/10/3/035003.
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Hwang, Priscilla Y., Jairaj Mathur, Yanyang Cao, Jose Almeida, Jiayu Ye, Vasilios Morikis, Daphne Cornish i in. "A Cdh3-β-catenin-laminin signaling axis in a subset of breast tumor leader cells control leader cell polarization and directional collective migration". Developmental Cell 58, nr 1 (styczeń 2023): 34–50. http://dx.doi.org/10.1016/j.devcel.2022.12.005.
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Yoon, Sungjun, i Rudolf E. Leube. "Keratin intermediate filaments: intermediaries of epithelial cell migration". Essays in Biochemistry 63, nr 5 (październik 2019): 521–33. http://dx.doi.org/10.1042/ebc20190017.
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Abstract Migration of epithelial cells is fundamental to multiple developmental processes, epithelial tissue morphogenesis and maintenance, wound healing and metastasis. While migrating epithelial cells utilize the basic acto-myosin based machinery as do other non-epithelial cells, they are distinguished by their copious keratin intermediate filament (KF) cytoskeleton, which comprises differentially expressed members of two large multigene families and presents highly complex patterns of post-translational modification. We will discuss how the unique mechanophysical and biochemical properties conferred by the different keratin isotypes and their modifications serve as finely tunable modulators of epithelial cell migration. We will furthermore argue that KFs together with their associated desmosomal cell–cell junctions and hemidesmosomal cell–extracellular matrix (ECM) adhesions serve as important counterbalances to the contractile acto-myosin apparatus either allowing and optimizing directed cell migration or preventing it. The differential keratin expression in leaders and followers of collectively migrating epithelial cell sheets provides a compelling example of isotype-specific keratin functions. Taken together, we conclude that the expression levels and specific combination of keratins impinge on cell migration by conferring biomechanical properties on any given epithelial cell affecting cytoplasmic viscoelasticity and adhesion to neighboring cells and the ECM.
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Adams, Gregory, Magdalena Preciado López, Alexander X. Cartagena-Rivera i Clare M. Waterman. "Survey of cancer cell anatomy in nonadhesive confinement reveals a role for filamin-A and fascin-1 in leader bleb–based migration". Molecular Biology of the Cell 32, nr 18 (19.08.2021): 1772–91. http://dx.doi.org/10.1091/mbc.e21-04-0174.
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We analyzed the localization of fluorescently tagged organelle-specific markers and actin-associated proteins in human melanoma and osteosarcoma cells undergoing leader bleb-based migration (LBBM) in nonadhesive confinement. It is also found that filamin-A and fascin-1 are important regulators in LBBM.
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Lavenus, Sandrine B., Sara M. Tudor, Maria F. Ullo, Karl W. Vosatka i Jeremy S. Logue. "A flexible network of vimentin intermediate filaments promotes migration of amoeboid cancer cells through confined environments". Journal of Biological Chemistry 295, nr 19 (31.03.2020): 6700–6709. http://dx.doi.org/10.1074/jbc.ra119.011537.
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Tumor cells can spread to distant sites through their ability to switch between mesenchymal and amoeboid (bleb-based) migration. Because of this difference, inhibitors of metastasis must account for each migration mode. However, the role of vimentin in amoeboid migration has not been determined. Because amoeboid leader bleb–based migration (LBBM) occurs in confined spaces and vimentin is known to strongly influence cell-mechanical properties, we hypothesized that a flexible vimentin network is required for fast amoeboid migration. To this end, here we determined the precise role of the vimentin intermediate filament system in regulating the migration of amoeboid human cancer cells. Vimentin is a classic marker of epithelial-to-mesenchymal transition and is therefore an ideal target for a metastasis inhibitor. Using a previously developed polydimethylsiloxane slab–based approach to confine cells, RNAi-based vimentin silencing, vimentin overexpression, pharmacological treatments, and measurements of cell stiffness, we found that RNAi-mediated depletion of vimentin increases LBBM by ∼50% compared with control cells and that vimentin overexpression and simvastatin-induced vimentin bundling inhibit fast amoeboid migration and proliferation. Importantly, these effects were independent of changes in actomyosin contractility. Our results indicate that a flexible vimentin intermediate filament network promotes LBBM of amoeboid cancer cells in confined environments and that vimentin bundling perturbs cell-mechanical properties and inhibits the invasive properties of cancer cells.
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MAREL, A. K., A. PIERA ALBEROLA i J. O. RÄDLER. "PROLIFERATION AND COLLECTIVE MIGRATION OF SMALL CELL GROUPS RELEASED FROM CIRCULAR PATCHES". Biophysical Reviews and Letters 07, nr 01n02 (czerwiec 2012): 15–28. http://dx.doi.org/10.1142/s1793048012500026.
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Collective cell migration is a key element in morphogenesis, cancer formation and wound healing. The multicellular dynamics of epithelial cell layers were studied in experiment and theory over the last years. Yet little is known about cell patches of finite size that should lead over from single cell behavior to collective motion. Here we study the migration and proliferation of small assemblies of epithelial cells (5-23 cells initially). Cells are released at defined time using removable poly(ethylene glycol)-dimethlacrylate (PEG-DMA) stencils with circular apertures, wherein cells were seeded. Using time-lapse microscopy we determine cell number, cell patch area and shape of multiple patches in parallel. We confirm exponential growth in cell number but find the area of the patches expanding faster than exponential in the early phase. The area is, however, well-described if cell proliferation is superimposed by elastic area dilation assuming that the cell groups were initially compressed. The elastic relaxation time is of the same order as the measured doubling time. Furthermore, analysis of the center-of-mass movement of the patches reveals bursts of directed motion, which coincide with asymmetric cell growth. In these cases the contours of the patches seem to result from a tug-of-war like scenario of opposing leader cells.
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Sampedro, María F., Gastón L. Miño, Carolina D. Galetto i Valeria Sigot. "Spatio-temporal analysis of collective migration in vivo by particle image velocimetry". Physical Biology 18, nr 6 (1.11.2021): 066008. http://dx.doi.org/10.1088/1478-3975/ac2e71.
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Abstract Collective cell migration drives the formation of complex organ systems as well as certain tumour invasions and wound healing processes. A characteristic feature of many migrating collectives is tissue-scale polarity, whereby ‘leader’ cells at the tissue edge guide ‘followers’ cells that become assembled into polarized epithelial tissues. In this study, we employed particle image velocimetry (PIV) as a tool to quantitate local dynamics underlying the migration of the posterior lateral line primordium (pLLP) in zebrafish at a short time scale. Epithelial cadherin-EGFP was the fluorescent tracer in time-lapse images for PIV analysis. At the tissue level, global speed and directionality of the primordium were extracted from spatially averaged velocity fields. Interestingly, fluctuating velocity patterns evolve at the mesoscale level, which distinguishes the pseudo-mesenchymal leading front from the epithelialized trailing edge, and superimpose to the global deceleration of the whole primordium during the separation of a protoneuromast. Local velocity fields obtained by PIV proved sensitive to estimate the migration speed and directionality of the pLLP in zebrafish, predicting protoneuromast separation at short time scales. Finally, the PIV approach may be suitable for analysing the dynamics of other in vivo models of collective migration.
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Rao, Megha Vaman, i Ronen Zaidel-Bar. "Formin-mediated actin polymerization at cell–cell junctions stabilizes E-cadherin and maintains monolayer integrity during wound repair". Molecular Biology of the Cell 27, nr 18 (15.09.2016): 2844–56. http://dx.doi.org/10.1091/mbc.e16-06-0429.
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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.
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Xu, Hui, Ding Ye, Martine Behra, Shawn Burgess, Songhai Chen i Fang Lin. "Gβ1 controls collective cell migration by regulating the protrusive activity of leader cells in the posterior lateral line primordium". Developmental Biology 385, nr 2 (styczeń 2014): 316–27. http://dx.doi.org/10.1016/j.ydbio.2013.10.027.
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Park, JinSeok, i Anthonios Chronopolous. "Abstract B029: Flip-flopping of fusion-positive rhabdomyosarcoma regulating intratumoral heterogeneity for metastasis". Clinical Cancer Research 28, nr 18_Supplement (15.09.2022): B029. http://dx.doi.org/10.1158/1557-3265.sarcomas22-b029.
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Abstract Of rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcoma, higher metastatic propensity of fusion-positive rhabdomyosarcoma (FPRMS), a subtype with PAX3-FOXO1 fusion gene, than fusion-negative subtype (FNRMS) suggest that the fusion gene may stimulate metastasis. Recent single-cell level research revealed that FPRMS has heterogeneity in the expression levels of the fusion gene, i.e., PAX3-FOXO1 fusion protein (P3F-FP) and corresponding phenotypes related to metastasis, e.g., higher cell motility of cells with low P3F-FP (FPLow). However, it remains unclear how the fusion gene and its heterogeneous expression regulate metastasis. Interestingly, FPRMS shows collective invasion, distinct from individual invasion of FNRMS. The collective invasion is prevalently observed in invasive tumors and has higher metastatic potentials than individual invasion. Despite its substantial commonality with well-characterized individual invasion, its features stemming from multi-cellular organization cause distinct features, potentially related to its higher metastatic potentials. Specifically, heterogeneity of a collective cell group, i.e., the leader/follower coordination, regulates collective invasion. The collective cell mass consists of “leaders,” trailblazing invasion paths, and “followers”, spreading through the paths despite their less invasiveness. At the initiation step of metastasis, the mass may enrich the subpopulation of leaders, driving collective invasion. However, it may revert the enrichment at the colonization step, suppressing migration and promoting colonization driven by followers at the secondary tumor site. This well-tuned process upon each metastasis step suggests the significance of dynamic switching between leaders/followers, regulating collective invasion and, in turn, metastasis. Here, we suggest bistability, a system with two stable states, represents the leader/follower coordination in FPRMS. The bistable system exhibits switch-like transitions between the states. i.e., “flip-flopping.” The flip-flopping enables even a small input to drive an “on/off” transition towards leaders or the other, implying the dynamic switching corresponding to each metastasis step. We discovered two distinct subpopulations with leader-like fast migrating FPLow/follower-like slow FPHigh cells, representing bistability in FPRMS. Specifically, the marginal region of FPRMS cell mass where leaders mainly reside showed higher subpopulation of fast FPLow cells. The bistability requires double-positive/negative feedback in the signaling, regulating flip-flopping. We found that YAP signaling may establish double-negative feedback with P3F-FP, modulating the flip-flopping. Thus, we suggest that the fusion gene functions as a toggle switch of bistability, and its "flip-flopping" modulation of expression by YAP signaling may designate cells as leaders or followers, regulating collective invasion and, thus, metastasis. This project will shed light on the metastasis of FPRMS, potentially leading us to suppress its metastasis. Citation Format: JinSeok Park, Anthonios Chronopolous. Flip-flopping of fusion-positive rhabdomyosarcoma regulating intratumoral heterogeneity for metastasis [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr B029.
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Sáenz-de-Santa-María, Inés, Lucía Celada, Andrés San José Martínez, Tamara Cubiella i María-Dolores Chiara. "Blockage of Squamous Cancer Cell Collective Invasion by FAK Inhibition Is Released by CAFs and MMP-2". Cancers 12, nr 12 (10.12.2020): 3708. http://dx.doi.org/10.3390/cancers12123708.
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Metastasis remains a clinically unsolved issue in cancer that is initiated by the acquisition of collective migratory properties of cancer cells. Phenotypic and functional heterogeneity that arise among cancer cells within the same tumor increase cellular plasticity and promote metastasis, however, their impact on collective cell migration is incompletely understood. Here, we show that in vitro collective cancer cell migration depends on FAK and MMP-2 and on the presence of cancer-associated fibroblasts (CAFs). The absence of functional FAK rendered cancer cells incapable of invading the surrounding stroma. However, CAFs and cancer cells over-expressing MMP-2 released FAK-deficient cells from this constraint by taking the leader positions in the invasive tracks, pushing FAK-deficient squamous cell carcinoma (SCC) cells towards the stroma and leading to the transformation of non-invasive cells into invasive cells. Our cell-based studies and the RNAseq data from the TCGA cohort of patients with head and neck squamous cell carcinomas reveal that, although both FAK and MMP-2 over-expression are associated with epithelial–mesenchymal transition, it is only MMP-2, not FAK, that functions as an independent prognostic factor. Given the significant role of MMP-2 in cancer dissemination, targeting of this molecule, better than FAK, presents a more promising opportunity to block metastasis.
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Loza, Andrew J., Sarita Koride, Gregory V. Schimizzi, Bo Li, Sean X. Sun i Gregory D. Longmore. "Cell density and actomyosin contractility control the organization of migrating collectives within an epithelium". Molecular Biology of the Cell 27, nr 22 (7.11.2016): 3459–70. http://dx.doi.org/10.1091/mbc.e16-05-0329.
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The mechanisms underlying collective migration are important for understanding development, wound healing, and tumor invasion. Here we focus on cell density to determine its role in collective migration. Our findings show that increasing cell density, as might be seen in cancer, transforms groups from broad collectives to small, narrow streams. Conversely, diminishing cell density, as might occur at a wound front, leads to large, broad collectives with a distinct leader–follower structure. Simulations identify force-sensitive contractility as a mediator of how density affects collectives, and guided by this prediction, we find that the baseline state of contractility can enhance or reduce organization. Finally, we test predictions from these data in an in vivo epithelium by using genetic manipulations to drive collective motion between predicted migratory phases. This work demonstrates how commonly altered cellular properties can prime groups of cells to adopt migration patterns that may be harnessed in health or exploited in disease.
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Doak, Andrea E., i Kevin J. Cheung. "Abstract P6-14-05: Regulation of cellular identity and spatial organization during collective breast cancer invasion". Cancer Research 83, nr 5_Supplement (1.03.2023): P6–14–05—P6–14–05. http://dx.doi.org/10.1158/1538-7445.sabcs22-p6-14-05.
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Abstract An early step in breast cancer progression is invasion of tumor cells into surrounding tissues. In many breast cancers, particularly ductal carcinomas, this invasion is accomplished by tumor cells migrating as a cohesive group. This often involves cells that take on heterogeneous roles as either leader or follower cells. While studies in common mouse and human breast cancer models have established that leader cells express high levels of keratin-14 (K14) and other basal epithelial markers, the molecular mechanisms regulating K14+ leader cell identity remain obscure. Here we performed time-sampled single cell RNA-sequencing in 3D type I collagen-embedded tumor organoids isolated from the MMTV-PyMT luminal B model of breast cancer. 11 distinct cellular transcriptional states were identified and correlated with K14 expression and invasive strand formation. Having identified the leader cell state we next asked what transcription factors were enriched, reasoning that transcription factors could be master regulators of leader cell fate. 30 different shRNAs targeting 10 genes were systematically evaluated for their effects on collective invasion. From this screen, suppression of Hes1, the downstream target of Notch signaling, yielded a marked switch from collective to single cell invasion. Disseminating single tumor cells maintained high expression of K14 in Hes1 knockdown organoids which was phenocopied by gamma-secretase inhibition in a human TNBC PDX model. Because K14+ tumor cells highly express the Notch ligand Jag1, these results support a model in which Notch signaling, specifically through activation of Hes1, dictates leader cell identity and spatial organization during collective invasion. Studies are ongoing investigating the impact of Hes1 dynamics on leader cell adhesion, hybrid EMT state, and preference for single versus collective metastasis. Because Notch suppression induces leader cell dissemination, we propose that Notch targeted therapy should be combined with therapies eradicating leader cells. Citation Format: Andrea E. Doak, Kevin J. Cheung. Regulation of cellular identity and spatial organization during collective breast cancer invasion. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-14-05.
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Doak, Andrea E., Rose Qu i Kevin J. Cheung. "Abstract A014: Transcriptional regulation of basal leader cell identity during collective breast cancer invasion". Cancer Research 83, nr 2_Supplement_2 (15.01.2023): A014. http://dx.doi.org/10.1158/1538-7445.metastasis22-a014.
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Abstract An early step in breast cancer progression is invasion of tumor cells into surrounding tissues. In many breast cancers, particularly ductal carcinomas, this invasion is accomplished by tumor cells migrating as a cohesive group. This often involves cells that take on heterogeneous roles as either leader or follower cells. Studies in common mouse and human breast cancer models have established that leader cells express high levels of keratin-14 (K14) and other basal epithelial markers. The presence of these K14+ cells promote metastasis and predict poor prognosis. The molecular mechanisms regulating K14+ leader cell identity and the methods for targeted depletion of these cells remain obscure. Here we performed time-sampled single cell RNA-sequencing in 3D type I collagen-embedded tumor organoids isolated from the MMTV-PyMT luminal B model of breast cancer. 11 distinct cellular transcriptional states were identified, and through correlation with K14 expression and invasive strand formation we classified one of the states as leader cells. Having confirmed the leader cell cluster markers spatially localize to the invasive front, we next asked which transcription factors were enriched, reasoning that transcription factors could be master regulators of leader cell fate. Three different shRNAs targeting ten genes were systematically evaluated for their effects on collective invasion and keratin-14 transcription. Each transcription factor was designated as either an invasion promoter or invasion suppressor depending on the correlation between transcription factor expression and organoid invasion. Studies are ongoing investigating the impact of invasion-promoting and invasion-suppressing transcription factors on cellular transcriptional states and metastatic dissemination in-vivo. We propose that targeting invasion-suppressing pathways could be combined with therapies that specifically target and eliminate K14+ invasive cells. To this end, we have identified multiple candidate druggable targets and specific surface markers expressed in K14+ invasive cells. Citation Format: Andrea E. Doak, Rose Qu, Kevin J. Cheung. Transcriptional regulation of basal leader cell identity during collective breast cancer invasion [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A014.
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Chrisafis, George, Tianhong Wang, Konstadinos Moissoglu, Alexander N. Gasparski, Yeap Ng, Roberto Weigert, Stephen J. Lockett i Stavroula Mili. "Collective cancer cell invasion requires RNA accumulation at the invasive front". Proceedings of the National Academy of Sciences 117, nr 44 (15.10.2020): 27423–34. http://dx.doi.org/10.1073/pnas.2010872117.
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Localization of RNAs at protrusive regions of cells is important for single-cell migration on two-dimensional surfaces. Protrusion-enriched RNAs encode factors linked to cancer progression, such as the RAB13 GTPase and the NET1 guanine nucleotide exchange factor, and are regulated by the tumor-suppressor protein APC. However, tumor cells in vivo often do not move as single cells but rather utilize collective modes of invasion and dissemination. Here, we developed an inducible system of three-dimensional (3D) collective invasion to study the behavior and importance of protrusion-enriched RNAs. We find that, strikingly, both theRAB13andNET1RNAs are enriched specifically at the invasive front of leader cells in invasive cell strands. This localization requires microtubules and coincides with sites of high laminin concentration. Indeed, laminin association and integrin engagement are required for RNA accumulation at the invasive front. Importantly, perturbing RNA accumulation reduces collective 3D invasion. Examination of in vivo tumors reveals a similar localization of theRAB13andNET1RNAs at potential invasive sites, suggesting that this mechanism could provide a targeting opportunity for interfering with collective cancer cell invasion.
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Guan, Liu-Yuan, Jian-Qing Lv, De-Qing Zhang i Bo Li. "Collective Polarization of Cancer Cells at the Monolayer Boundary". Micromachines 12, nr 2 (22.01.2021): 112. http://dx.doi.org/10.3390/mi12020112.
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Cell polarization, a process depending on both intracellular and intercellular interactions, is crucial for collective cell migration that commonly emerges in embryonic development, tissue morphogenesis, wound healing and cancer metastasis. Although invasive cancer cells display weak cell–cell interactions, they can invade host tissues through a collective mode. Yet, how cancer cells without stable cell–cell junctions polarize collectively to migrate and invade is not fully understood. Here, using a wound-healing assay, we elucidate the polarization of carcinoma cells at the population level. We show that with loose intercellular connections, the highly polarized leader cells can induce the polarization of following cancer cells and subsequent transmission of polarity information by membrane protrusions, leading to gradient polarization at the monolayer boundary. Unlike the polarization of epithelial monolayer where Rac1/Cdc42 pathway functions primarily, our data show that collective polarization of carcinoma cells is predominantly controlled by Golgi apparatus, a disruption of which results in the destruction of collective polarization over a large scale. We reveal that the Golgi apparatus can sustain membrane protrusion formation, polarized secretion, intracellular trafficking, and F-actin polarization, which contribute to collective cancer cell polarization and its transmission between cells. These findings could advance our understanding of collective cancer invasion in tumors.
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Vogel, B. E., i E. M. Hedgecock. "Hemicentin, a conserved extracellular member of the immunoglobulin superfamily, organizes epithelial and other cell attachments into oriented line-shaped junctions". Development 128, nr 6 (15.03.2001): 883–94. http://dx.doi.org/10.1242/dev.128.6.883.
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him-4 mutations cause a novel syndrome of tissue fragility, defective cell migration and chromosome instability in Caenorhabditis elegans. Null mutants have abnormal escape reflex, mispositioning of the vas deferens and uterus, and mitotic chromosome loss and multinucleate cells in the germline. The him-4 gene product, hemicentin, is a conserved extracellular matrix protein with 48 tandem immunoglobulin repeats flanked by novel terminal domains. Secreted from skeletal muscle and gonadal leader cells, hemicentin assembles into fine tracks at specific sites, where it contracts broad regions of cell contact into oriented linear junctions. Some tracks organize hemidesmosomes in the overlying epidermis. Hemicentin tracks facilitate mechanosensory neuron anchorage to the epidermis, gliding of the developing gonad along epithelial basement membranes and germline cellularization.
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Abdellatef, Shimaa A., i Jun Nakanishi. "Photoactivatable substrates for systematic study of the impact of an extracellular matrix ligand on appearance of leader cells in collective cell migration". Biomaterials 169 (lipiec 2018): 72–84. http://dx.doi.org/10.1016/j.biomaterials.2018.03.045.
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Yokoyama, Sho, Tsubasa S. Matsui i Shinji Deguchi. "New wrinkling substrate assay reveals traction force fields of leader and follower cells undergoing collective migration". Biochemical and Biophysical Research Communications 482, nr 4 (styczeń 2017): 975–79. http://dx.doi.org/10.1016/j.bbrc.2016.11.142.
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Kang, J. H., S. Ahamed, K. H. Sa, S. W. Han i Y. M. Kang. "THU0077 CADHERINS GUIDE THE DIRECTIONAL MIGRATION OF THE SYNOVIOCYTES IN RHEUMATOID ARTHRITIS". Annals of the Rheumatic Diseases 79, Suppl 1 (czerwiec 2020): 251.3–251. http://dx.doi.org/10.1136/annrheumdis-2020-eular.6426.
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Background:Aggressiveness of synoviocytes and collective migration of organized synovial tissues play a key role in the pathogenesis of pannus invasion into adjacent joint structure. Interactions among synovial cells for grouped movement, however, have not been properly elucidated.Objectives:We hypothesized that cadherins which have functions on the synovial invasion in RA, may play a critical role in collective migration of rheumatoid synoviocytes.Methods:Cadherins expression patterns on the synoviocytes isolated from patients with RA were evaluated using RT-PCR, flow cytometry, and western blot analysis. Mesenchymal and epithelial phenotypes were examined in cadherin overexpressing cell line by flow cytometry. L-cells with overexpression of CDH2 (CDH2hi), CDH11 (CDH11hi), and combination of CDH2/CDH11 (CDH2hi/CDH11hi) were prepared. Migration of cells was observed by taking time-lapse images with laser confocal microscope.In vitrocollective migration and directional movement in response to inflammatory mediators and different matrix rigidity were evaluated.In vivohoming of CDH2hi/CDH11hi-L-cells into joint tissues was performed in collagen induced arthritis (CIA) mouse. In vivoandex vivomigration pattern of CDH11hi-L-cells were investigated in nude mice using optical imaging system.Results:In rheumatoid synovial tissues, CDH2 and CDH11 were highly expressed compared to synovial tissues from osteoarthritis. CDH2 and CDH11 were also highly expressed on synovial fibroblasts isolated from RA. Phenotype analysis of mesenchymal and epithelial cells in CDH11hi-L-cells and CDH2hi/CDH11hi-L-cells showed increased expression of α5β1, CD44s, vimentin, and α-SMA compared with MOCK-L-cells. We then analyzed the pattern of migration of MOCK, CDH2hi, CDH11hi, and CDH2hi/CDH11hi-L-cells using time lapse images. During migration over a hard ECM, CDH2hiand CDH11hi-L cells represented higher aspect ratio compare to a soft ECM. Aspect ratio relatively found lower in CDH2hi/CDH11hi-L-cell lines than MOCK cells. CDH2hi/CDH11hi-L-cells showed significantly higher migration velocity and Euclidean distance with narrower angle of migratory directions in a cytokine mediated migration. Compared to the MOCK cells, persistence ratio and aspect ratio of migration were also higher in CDH2hi, CDH11hi, and CDH2hi/CDH11hi-L-cells. CDH2hi/CDH11hi-L-cells collectively migrated with the formation of leader and follower cells. In a chemokine mediated hard stiffness of ECM, durotaxis was observed in CDH11hi-L-cells. After 24 hours of intraarticular knee injection in CIA mouse, higher number of CDH2hi/CDH11hi-L-cells invaded into the cartilage than MOCK cells.In vivomigration of CDH2hi/CDH11hi-L-cells was also found towards the chemokine and cartilage mixed matrigel plug in the subcutaneous space of mice.Conclusion:The expression of CDH2 and CDH11 promotes directional migration of synoviocytes, indicating the potential role of these cadherins on the pannus tissues in the invasion into adjacent joint structure in RA.References:[1]Noss EH, Chang SK, Watts GFM, Brenner MB. Cadherin-11 engagement modulates matrix metalloproteinase production by rheumatoid arthritis synovial fibroblasts. Arthritis Rheum. 2011 Dec; 63(12): 3768–3778Disclosure of Interests:None declared
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Xia, Feng, Wei Xia i Xudong Yu. "LncRNA HOTAIR Influences the Growth, Migration, and Invasion of Papillary Thyroid Carcinoma via Affection on the miR-488-5p/NUP205 Axis". Technology in Cancer Research & Treatment 19 (1.01.2020): 153303382096212. http://dx.doi.org/10.1177/1533033820962125.
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Objective: The study was aim to investigate the effect of HOX transcript antisense RNA (HOTAIR) on the growth, migration, and invasion of papillary thyroid carcinoma (PTC) and its underlying mechanisms. Methods: Cell growth, invasion, and migration was respectively investigated using the MTT assay, trans-well assay, and wound healing assay. The expression of genes and proteins was respectively determined by Western blot analysis and RT-PCR experiments. Results: It was demonstrated that high expression of HOTAIR in PTC cells (BCPAP) and tissues resulted in fast tumor growth and poor survival time of the PTC-bearing mice models. Moreover, overexpression of HOTAIR leaded to markedly enhanced proliferation, migration, and invasion of BCPAP cells. Increase the levels of HOTAIR in BCPAP cells signally down-regulated the miR-488-5p levels which was able of inhibiting the growth rate, increasing the apoptosis rate, and decreasing the invasion/migration ability of BCPAP cells. Further studies indicated that HOTAIR promoted BCPAP cell growth, invasion, and migration mainly through regulating the miR-488-5p/NUP205 axis and the levels of Bcl-2 as well. Conclusion: HOTAIR promoted the growth, migration, and invasion of papillary thyroid carcinoma mainly through regulating the miR-488-5p/NUP205 axis.
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Imanishi, Ayaka, Yuma Aoki, Masaki Kakehi, Shunsuke Mori, Tomomi Takano, Yukihiko Kubota, Hon-Song Kim, Yukimasa Shibata i Kiyoji Nishiwaki. "Genetic interactions among ADAMTS metalloproteases and basement membrane molecules in cell migration in Caenorhabditis elegans". PLOS ONE 15, nr 12 (2.12.2020): e0240571. http://dx.doi.org/10.1371/journal.pone.0240571.
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During development of the Caenorhabditis elegans gonad, the gonadal leader cells, called distal tip cells (DTCs), migrate in a U-shaped pattern to form the U-shaped gonad arms. The ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) family metalloproteases MIG-17 and GON-1 are required for correct DTC migration. Mutations in mig-17 result in misshapen gonads due to the misdirected DTC migration, and mutations in gon-1 result in shortened and swollen gonads due to the premature termination of DTC migration. Although the phenotypes shown by mig-17 and gon-1 mutants are very different from one another, mutations that result in amino acid substitutions in the same basement membrane protein genes, emb-9/collagen IV a1, let-2/collagen IV a2 and fbl-1/fibulin-1, were identified as genetic suppressors of mig-17 and gon-1 mutants. To understand the roles shared by these two proteases, we examined the effects of the mig-17 suppressors on gon-1 and the effects of the gon-1 suppressors and enhancers on mig-17 gonadal defects. Some of the emb-9, let-2 and fbl-1 mutations suppressed both mig-17 and gon-1, whereas others acted only on mig-17 or gon-1. These results suggest that mig-17 and gon-1 have their specific functions as well as functions commonly shared between them for gonad formation. The levels of collagen IV accumulation in the DTC basement membrane were significantly higher in the gon-1 mutants as compared with wild type and were reduced to the wild-type levels when combined with suppressor mutations, but not with enhancer mutations, suggesting that the ability to reduce collagen IV levels is important for gon-1 suppression.
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Hardt, Melina, Kurt Zatloukal i Helmut H. Popper. "Abstract 3614: 3D model to study migration and invasion of lung cancer". Cancer Research 83, nr 7_Supplement (4.04.2023): 3614. http://dx.doi.org/10.1158/1538-7445.am2023-3614.
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Abstract Background: In 2D cell cultures, migration of tumor cells is characterized by epithelial-to-mesenchymal transition (EMT), whereby tumor cells loose epithelial and express mesenchymal markers and very often change into a spindle cell phenotype. In contrast to 2D cultures, in 3D cultures tumor cells do not lose their differentiation. Small cell lung cancer usually moves as single cells or in small clusters, squamous cell and adenocarcinomas preferentially move in large clusters of cells. In tissue specimen, all of these carcinomas migrate in a hybrid EMT, not loosing their cytokeratin and E-cadherin expression. In AC and SCC also polarity and specification do occur, as some tumor cells act as leaders, providing orientation for the followers. However, 3D culture system might better depict real migration and come closer to the in vivo system as 2D cell culture systems. Material and Method: A 3D bioprinter (TissueLabsR) was used to spot an alveolar-mimicking lung-specific matrix on cell culture wells. Microscopic channels out of pluronicsR are created within the matrix. Pluronics is removed by cooling, leaving empty channels within the protein matrix. These channels can be filled with different interleukins, such as IL23, which will direct migration of the tumor cells. Cultured cell lines from an adenocarcinoma (A549) and small cell carcinoma (NCI-H82) are layered on top of the matrix and migration into the matrix is studied using different time points. Results and Discussion: A matrix simulating an alveolar structure was created with MatrigelR. The A549 cells were seeded on the matrix and grown for 2,5, 10, and 14 days. The cells formed cell clusters on the matrix and after one week started to invade the matrix in cell complexes. By immunohistochemistry we could show, that the A549 cells retained their epithelial differentiation. The H82 cells showed a different behavior. They did not form large clusters, but started to invade in small groups. The use of the bioprinter enabled us not only to create a 3D tumor culture system to simulate the in vivo conditions but also to create matrix structures for studying invasion and migration and to stimulate carcinoma cells with migration-activating substances. Citation Format: Melina Hardt, Kurt Zatloukal, Helmut H. Popper. 3D model to study migration and invasion of lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3614.
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Hemmings-Mieszczak, Maja, Thomas Hohn i Thomas Preiss. "Termination and Peptide Release at the Upstream Open Reading Frame Are Required for Downstream Translation on Synthetic Shunt-Competent mRNA Leaders". Molecular and Cellular Biology 20, nr 17 (1.09.2000): 6212–23. http://dx.doi.org/10.1128/mcb.20.17.6212-6223.2000.
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ABSTRACT We have shown recently that a stable hairpin preceded by a short upstream open reading frame (uORF) promotes nonlinear ribosome migration or ribosome shunt on a synthetic mRNA leader (M. Hemmings-Mieszczak and T. Hohn, RNA 5:1149–1157, 1999). We have now used the model mRNA leader to study further the mechanism of shunting in vivo and in vitro. We show that a full cycle of translation of the uORF, including initiation, elongation, and termination, is a precondition for the ribosome shunt across the stem structure to initiate translation downstream. Specifically, AUG recognition and the proper release of the nascent peptide are necessary and sufficient for shunting. Furthermore, the stop codon context must not impede downstream reinitiation. Translation of the main ORF was inhibited by replacement of the uORF by coding sequences repressing reinitiation but stimulated by the presence of the virus-specific translational transactivator of reinitiation (cauliflower mosaic virus pVI). Our results indicate reinitiation as the mechanism of translation initiation on the synthetic shunt-competent mRNA leader and suggest that uORF-dependent shunting is more prevalent than previously anticipated. Within the above constraints, uORF-dependent shunting is quite tolerant of uORF and stem sequences and operates in systems as diverse as plants and fungi.
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Schaniel, Christoph, Evangelia Pardali, Federica Sallusto, Mattheos Speletas, Christiane Ruedl, Takeyuki Shimizu, Thomas Seidl i in. "Activated Murine B Lymphocytes and Dendritic Cells Produce a Novel CC Chemokine which Acts Selectively on Activated T Cells". Journal of Experimental Medicine 188, nr 3 (3.08.1998): 451–63. http://dx.doi.org/10.1084/jem.188.3.451.
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Genes were isolated using the suppression subtractive hybridization method by stimulation of pro/pre B cells with anti-CD40 and interleukin (IL)-4 to mature Sμ-Sε–switched cells. One of the strongly upregulated genes encodes a novel murine CC chemokine we have named ABCD-1. The ABCD-1 gene has three exons separated by 1.2- and 2.7-kb introns. It gives rise to a 2.2-kb transcript containing an open reading frame of 276 nucleotides. Two polyadenylation sites are used, giving rise to cDNAs with either 1550 or 1850 bp of 3′ untranslated regions. The open reading frame encodes a 24 amino acid–long leader peptide and a 68 amino acid–long mature protein with a predicted molecular mass of 7.8 kD. ABCD-1 mRNA is found in highest quantities in activated splenic B lymphocytes and dendritic cells. Little chemokine mRNA is present in lung, in unstimulated splenic cells, in thymocytes, and in lymph node cells. No ABCD-1 mRNA is detected in bone marrow, liver, kidney, or brain, in peritoneal exudate cells as well as in the majority of all unstimulated B lineage cells tested. It is also undetectable in Concanavalin A–activated/IL-2–restimulated splenic T cells, and in bone marrow–derived IL-2–induced natural killer cells and IL-3–activated macrophages. Recombinant ABCD-1 revealed a concentration-dependent and specific migration of activated splenic T lymphoblasts in chemotaxis assays. FACS® analyses of migrated cells showed no preferential difference in migration of CD4+ versus CD8+ T cell blasts. Murine as well as human T cells responded to ABCD-1. Freshly isolated cells from bone marrow, thymus, spleen, and lymph node, IL-2–activated NK cells, and LPS-stimulated splenic cells, all did not show any chemotactic response. Thus, ABCD-1 is the first chemokine produced in large amounts by activated B cells and acting selectively on activated T lymphocytes. Therefore, ABCD-1 is expected to play an important role in the collaboration of dendritic cells and B lymphocytes with T cells in immune responses.
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Bayley, Douglas P., i Ken F. Jarrell. "Overexpression of Methanococcus voltaeFlagellin Subunits in Escherichia coli and Pseudomonas aeruginosa: a Source of Archaeal Preflagellin". Journal of Bacteriology 181, nr 14 (15.07.1999): 4146–53. http://dx.doi.org/10.1128/jb.181.14.4146-4153.1999.
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ABSTRACT Methanococcus voltae is a flagellated member of theArchaea. Four highly similar flagellin genes have previously been cloned and sequenced, and the presence of leader peptides has been demonstrated. While the flagellins of M. voltae are predicted from their gene sequences to be approximately 22 to 25 kDa, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis of purified flagella revealed flagellin subunits with apparent molecular masses of 31 and 33 kDa. Here we describe the expression of a M. voltae flagellin in the bacteria Escherichia coli and Pseudomonas aeruginosa. Both of these systems successfully generated a specific expression product with an apparently uncleaved leader peptide migrating at approximately 26.5 kDa. This source of preflagellin was used to detect the presence of preflagellin peptidase activity in the membranes of M. voltae. In addition to the native flagellin, a hybrid flagellin gene containing the sequence encoding theM. voltae FlaB2 mature protein fused to the P. aeruginosa pilin (PilA) leader peptide was constructed and transformed into both wild-type P. aeruginosa and a prepilin peptidase (pilD) mutant of P. aeruginosa. Based on migration in SDS-PAGE, the leader peptide appeared to be cleaved in the wild-type cells. However, the archaeal flagellin could not be detected by immunoblotting when expressed in thepilD mutant, indicating a role of the peptidase in the ultimate stability of the fusion product. When the +5 position of the mature flagellin portion of the pilin-flagellin fusion was changed from glycine to glutamic acid (as in the P. aeruginosa pilin) and expressed in both wild-type and pilD mutant P. aeruginosa, the product detected by immunoblotting migrated slightly more slowly in the pilD mutant, indicating that the fusion was likely processed by the prepilin peptidase present in the wild type. Potential assembly of the cleaved fusion product by the type IV pilin assembly system in a P. aeruginosaPilA-deficient strain was tested, but no filaments were noted on the cell surface by electron microscopy.
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Wilson, Amy L., Brittany R. Doran, Bashirah Basri, Laura R. Moffitt, Magdalena Plebanski, Andrew N. Stephens i Maree Bilandzic. "Abstract B040: Leader cells mediate tumor engraftment and promote immunosuppression to drive ovarian cancer progression in vivo". Cancer Research 83, nr 2_Supplement_2 (15.01.2023): B040. http://dx.doi.org/10.1158/1538-7445.metastasis22-b040.
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Abstract Epithelial ovarian cancer (EOC) is most frequently diagnosed at an advanced stage, and is characterized by its high recurrence rate and almost-universal acquisition of chemoresistance. Metastasis of EOC is driven by heterogenous spheroids that passively disseminate throughout the peritoneal cavity, promoting tumor spread and recurrence. We previously identified a sub-population of highly motile and invasive “Leader cells” (LCs) that express the basal epithelial protein KRT14 as an absolute determinant of invasive potential. We demonstrated KRT14 knockout in EOC cells does not impact viability or proliferation, however completely ablates their ability to invade through Matrigel in 2D and 3D format in vitro. Although a role for LCs in mesothelial clearance and invasion has been established, these mechanisms remain poorly understood. Here we show a critical role for KRT14+ LCs in immunosuppression and tumor-immune privilege in vivo. In the ID8 syngeneic EOC mouse model, tumor-specific LC (KRT14) loss (LCKO) impaired ovarian intrabursal primary tumor engraftment and subsequent metastatic spread. Immune phenotyping by flow cytometry revealed that mice bearing LCKO tumors displayed decreased proportions of immunosuppressive tumor-adjacent Tregs and M2 macrophages, and improved CD8+ T-cell/Treg ratios. Conversely, forced LC-overexpression (LCOE) in EOC tumors accelerated metastasis, and promoted tumor-immune evasion via upregulated secretion of suppressive chemokines including CCL22 and CCL5. In addition to their critical role in migration and invasion, the current study provides in vivo evidence that leader cells are mediators of immune suppression in ovarian cancer. This work supports the basis that defining novel strategies to target LCs to promote anti-tumor immunity and limit metastatic progression may be a useful strategy for improved epithelial ovarian cancer therapy. Citation Format: Amy L. Wilson, Brittany R. Doran, Bashirah Basri, Laura R. Moffitt, Magdalena Plebanski, Andrew N. Stephens, Maree Bilandzic. Leader cells mediate tumor engraftment and promote immunosuppression to drive ovarian cancer progression in vivo [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B040.
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Leggett, Susan E., Zachary J. Neronha, Dhananjay Bhaskar, Jea Yun Sim, Theodora Myrto Perdikari i Ian Y. Wong. "Motility-limited aggregation of mammary epithelial cells into fractal-like clusters". Proceedings of the National Academy of Sciences 116, nr 35 (14.08.2019): 17298–306. http://dx.doi.org/10.1073/pnas.1905958116.
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Migratory cells transition between dispersed individuals and multicellular collectives during development, wound healing, and cancer. These transitions are associated with coordinated behaviors as well as arrested motility at high cell densities, but remain poorly understood at lower cell densities. Here, we show that dispersed mammary epithelial cells organize into arrested, fractal-like clusters at low density in reduced epidermal growth factor (EGF). These clusters exhibit a branched architecture with a fractal dimension of Df=1.7, reminiscent of diffusion-limited aggregation of nonliving colloidal particles. First, cells display diminished motility in reduced EGF, which permits irreversible adhesion upon cell–cell contact. Subsequently, leader cells emerge that guide collectively migrating strands and connect clusters into space-filling networks. Thus, this living system exhibits gelation-like arrest at low cell densities, analogous to the glass-like arrest of epithelial monolayers at high cell densities. We quantitatively capture these behaviors with a jamming-like phase diagram based on local cell density and EGF. These individual to collective transitions represent an intriguing link between living and nonliving systems, with potential relevance for epithelial morphogenesis into branched architectures.