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Choi, Mi-Yon. "P53 mediated cell motility in H1299 lung cancer cells". VCU Scholars Compass, 2010. http://scholarscompass.vcu.edu/etd/109.
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Studies have shown that gain-of- function mutant p53, AKT, and NFκB promote invasion and metastasis in tumor cells. Signals transduced by AKT and p53 are integrated via negative feedback between the two pathways. Tumor derived p53 was also indicated to induce NFκB gene expression. Due to the close relationship between p53/AKT and p53/NFκB, we hypothesized that AKT and NFκB can enhance motility in cells expressing mutant p53. Effects on cell motility were determined by scratch assays. CXCL5- chemokine is also known to induce cell motility. We hypothesized that enhanced cell motility by AKT and NFκB is mediated, in part, by CXCL5. CXCL5 expression levels in the presence and absence of inhibitors were determined by qRT-PCR. We also hypothesized that gain-of-function mutant p53 contributes to the activation of AKT. The effect of mutant p53 on AKT phosphorylation was investigated with a Ponasterone A- inducible mutant cell line (H1299/R175H) and vector control. These results indicated that AKT and NFκB enhance motility in cells expressing mutant p53 and this enhanced motility is, in part, mediated by CXCL5. However, AKT phosphorylation was independent of mutant p53.
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Garg, Ayush A. "Electromagnetic Fields Alter the Motility of Metastatic Breast Cancer Cells". The Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1563816767104018.
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Adla, Shalini. "Characterization of the neural cell recognition molecule L1 in breast cancer cells and its role in breast cancer cell motility". Access to citation, abstract and download form provided by ProQuest Information and Learning Company; downloadable PDF file, 125 p, 2008. http://proquest.umi.com/pqdweb?did=1459905751&sid=5&Fmt=2&clientId=8331&RQT=309&VName=PQD.
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Seller, Zerrin. "Role of #alpha#4#beta#1-mediated signalling in malignant melanoma adhesion and motility". Thesis, King's College London (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266520.
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Tian, Jing. "Inhibition of melanoma cell motility by the snake venom disintegrin eristostatin". Access to citation, abstract and download form provided by ProQuest Information and Learning Company; downloadable PDF file, 61 p, 2007. http://proquest.umi.com/pqdweb?did=1397900451&sid=10&Fmt=2&clientId=8331&RQT=309&VName=PQD.
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Ahmad, Omaima Farid. "The Role of Filamin A in Cell Motility, Adhesion and Invasion in Ovarian Cancer Cells". University of Toledo Honors Theses / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=uthonors1503407822068426.
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Wright, Adele Hart. "The role of integrins in the differential upregulation of tumor cell motility by endothelial extracellular matrix proteins". Diss., Georgia Institute of Technology, 1999. http://hdl.handle.net/1853/17352.
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Hoppe, Andreas. "Adaptive spline method for the assessment of cell motility and its application to lesions". Thesis, University of South Wales, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.341937.
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Di, Kaijun, i 狄凱軍. "The role of Id-1 on the proliferation, motility and mitotic regulationof prostate epithelial cells". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B38944704.
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Patel, Sabina. "The Development of Tetracycline Dependent Pancreatic Cancer Cells and the Evaluation of CapG and Gelsolin Expression on Pancreatic Cancer Cell Motility In Vitro". Thesis, University of Liverpool, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.491370.
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Precise control of the level of protein expression in cells can facilitate functional studies providing information on the role of given proteins. In this thesis, I describe the generation of tetracycline-inducible pancreatic cancer cells and the subsequent use of these in the functional characterisation of an actin capping protein, CapG. Such cells were obtained in three pancreatic cancer cell lines, Panc-I, Suit-2 and MiaPaCa-2 cells through consecutive transfections with two plasmid constructs. The first of these harboured a second-generation reverse tetracycline-controlled transactivator protein (rtTA) whilst the second, contained the gene of interest (CapG or luciferase) under the control of a tetracycline response promoter element (pTRE). Suit-2 derived tetracycline inducible clones, along with stable doxycycline-inducible hepatoma cell lines, were used to study the effect of modulating CapG expression on cell motility. Here I report that stable introduction of a pTRE2hygCapG construct into two doxycycline-inducible clones derived from Suit-2 cells, Suit-2 ptet1I and Suit-2 ptet29 clones resulted in a dose and time-dependent increase of CapG expression in response to doxycycline. Moreover, doxycycline-mediated upregulation of CapG expression led to a significant increase in the wound healing capacity of Suit-2 ptet29 cells. The expression of a related actin binding and cell motility protein, gelsolin was also determined. Immunostaining of benign (n=24 patients) and malignant (n=68 patients) pancreatic ductal cells revealed higher gelsolin expression in the malignant state (P
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Paiwand, Frouz Frozan. "RHAMM, CD44 expression and erk activation are linked in malignant human breast cancer cells and are associated with cell motility". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp01/MQ46047.pdf.
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Peng, Zhengang, Jennifer Weber, Zhaosheng Han, Rulong Shen, Wenchao Zhou, James Scott, Michael Chan i Huey-Jen Lin. "Dichotomy effects of Akt signaling in breast cancer". BioMed Central, 2012. http://hdl.handle.net/10150/610205.
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BACKGROUND:The oncogenic roles contributed by the Akt/PKB kinase family remain controversial and presumably depend on cell context, but are perceived to be modulated by an interplay and net balance between various isoforms. This study is intended to decipher whether distinct Akt kinase isoforms exert either redundant or unique functions in regulating neoplastic features of breast cancer cells, including epithelial-mesenchymal transition (EMT), cell motility, and stem/progenitor cell expansion.RESULTS:We demonstrate that overactivation of Akt signaling in nonmalignant MCF10A cells and in primary cultures of normal human mammary epithelial tissue results in previously unreported inhibitory effects on EMT, cell motility and stem/progenitor cell expansion. Importantly, this effect is largely redundant and independent of Akt isoform types. However, using a series of isogenic cell lines derived from MCF-10A cells but exhibiting varying stages of progressive tumorigenesis, we observe that this inhibition of neoplastic behavior can be reversed in epithelial cells that have advanced to a highly malignant state. In contrast to the tumor suppressive properties of Akt, activated Akt signaling in MCF10A cells can rescue cell viability upon treatment with cytotoxic agents. This feature is regarded as tumor-promoting.CONCLUSION:We demonstrate that Akt signaling conveys novel dichotomy effects in which its oncogenic properties contributes mainly to sustaining cell viability, as opposed to the its tumor suppressing effects, which are mediated by repressing EMT, cell motility, and stem/progenitor cell expansion. While the former exerts a tumor-enhancing effect, the latter merely acts as a safeguard by restraining epithelial cells at the primary sites until metastatic spread can be moved forward, a process that is presumably dictated by the permissive tumor microenvironment or additional oncogenic insults.
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Bailey, Kelly M. "Focal adhesion kinase mediates caveolin-1 expression during epithelial to mesenchymal transition a novel pathway regulating aspects of cell motility in cancer /". Morgantown, W. Va. : [West Virginia University Libraries], 2008. https://eidr.wvu.edu/etd/documentdata.eTD?documentid=5804.
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Thesis (Ph. D.)--West Virginia University, 2008.Title from document title page. Document formatted into pages; contains x, 229 p. : ill. (some col.). Includes abstract. Includes bibliographical references.
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Webster, Rebecca. "Complementary investigations of the molecular biology of cancer : assessment of the role of Grb7 in the proliferation and migration of breast cancer cells; and prediction and validation of microRNA targets involved in cancer". University of Western Australia. School of Medicine and Pharmacology, 2008. http://theses.library.uwa.edu.au/adt-WU2008.0179.
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[Truncated abstract] For this thesis, the molecular biology of cancer was approached from two directions. Firstly, an investigation was conducted on the role of growth factor receptor-bound protein 7 (Grb7) in breast cancer. Grb7 is an adapter molecule that binds to a variety of proteins, including the growth factor receptor and proto-oncogene, ErbB2, and mediates signalling to downstream pathways. It has been linked to cell migration and an invasive phenotype, and is of interest as a therapeutic target. To investigate the role of Grb7 in breast cancer, preliminary experiments were performed that, firstly, determined the expression of wild-type Grb7 and a splice variant, Grb7V, in a range of cell lines, and secondly, aided the development of a protocol for treating cells with short interfering RNA (siRNA) against Grb7 and the ErbB ligand, heregulin (HRG), in a cell system appropriate for measuring the functional outcomes. Using this protocol in conjunction with CellTitre (CT) proliferation assays, it was demonstrated that Grb7 does not play a role in the proliferation of either unstimulated or HRG-stimulated SK-BR-3 breast cancer cells. Furthermore, using the protocol in conjunction with Boyden chamber migration assays, it was shown that inhibition of Grb7 expression has a slight stimulatory effect on HRG-stimulated SK-BR-3 cell migration. Thus, Grb7 was found to play only a minor role in the migration of SK-BR-3 cells, suggesting that it is not an ideal anti-cancer target for breast cancers modelled by this cell system. Concurrently, a second investigation was conducted, which similarly sought insight into the molecular biology of cancer, but adopted a more strategic approach. ... These results provide evidence for a biologically significant role for the miR-7-mediated regulation of EGFR expression. A microarray experiment was also performed to identify genes that were down-regulated following treatment with miR-7 compared to NS precursor. Of 248 down-regulated genes, including EGFR, 37 promising new miR-7 target candidates were identified. Functional clustering of down-regulated genes and promising target candidates suggested that miR-7 may have functionally-related targets involved in processes including cell motility and brain-associated functions. This investigation thus yielded a program capable of accurately predicting a miRNA target not predicted by any other target prediction program, verified a previously unknown miRNA:target interaction with functional consequences in cancer cells and provided the first steps towards investigating miR-7-mediated regulation in greater depth. Furthermore, EGFR was, to our knowledge, the first example of a verified miRNA target with target sites that are not conserved across mammals, an observation with important implications for computational target prediction and the evolution of miRNA regulatory systems. In addition, the demonstrated growth inhibitory and cytotoxic effects of miR-7 on lung cancer cells raise the possibility of a miR-7-based therapeutic for the treatment of EGFR-overexpressing tumours.
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Zhao, Rathje Li-Sophie. "Tropomyosin in Normal and Malignant Cells and the Action of Picropodophyllin on the Microfilament and Microtubule Systems". Doctoral thesis, Stockholms universitet, Wenner-Grens institut, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-27767.
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Cell motility is a fundamental process, enabling cells to migrate, for instance during embryogenesis, tissue repair and defense. Force is generated by two protein systems, which also participate in cell proliferation, control macromolecular and organelle distribution and determine the fine structure of the cell interior. The major components of these are actin and tubulin, respectively, and they are referred to as the microfilament and the microtubule systems. This thesis focuses on tropomyosin, one of many microfilament associated proteins coupled to actin dynamics and organization and expressed in several isoform variants. Altered distribution and isoform expression of tropomyosin are signatures of malignant cells and are dealt with in the current thesis. The presence of tropomyosin isoforms in protruding lamellipodia of migrating cells is demonstrated, and a method to fractionate tropomyosin depending on its organization in an easily extractable, and a more tightly bound cytoplasmic form is presented. Analysis of the loosely associated tropomyosin fraction by gel filtration chromatography revealed that most of the tropomyosins in this fraction exist in a multimeric form. It was also observed that the distribution of tropomyosin varied between non-transformed and transformed cells with most of the isoforms enriched in the loosely bound fraction in the latter category of cells. Possibly this reflects the extensive reorganization of the microfilament system observed in cancer cells and which, depending on the context, can be normalized by introduction of certain tropomyosin isoforms. Many anti-cancer drugs target the microtubule system, inhibit cell division and promote apoptosis. Here it is shown that picropodophyllin, which has promising anticancer properties has a destabilizing effect on microtubules and via the microfilament system causes cells to detach from their substratum. Furthermore, picropodophyllin interferes with stimulation of the insulin-like growth factor receptor, which is involved in growth stimulation, differentiation and survival and whose expression is up-regulated in cancer cells.
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Adanja, Ivan. "Automated tracking of unmarked cells migrating in three-dimensional matrices". Doctoral thesis, Universite Libre de Bruxelles, 2012. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209703.
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The goal of this thesis is the development of a tracking algorithm for populations of unmarked cancer cells that migrate in 3D in vitro gels. The tracking algorithm is intended to be a tool for analysing the motility of large population (i.e. hundreds) of cells in the context of the anti-migratory drug development and more specifically drug screening. In oncology, cancer cell migration plays pivotal roles in the spread of cancer cells from a primary tumor site to neighboring and secondary sites, i.e. the processes of tissue invasion and metastasis. Preventing such processes represents an important therapeutic approach to cancer treatment. Providing tools able to test potential anti-migratory drugs thus constitutes currently a real need in oncology therapy. The goal of drug screening in this context aims to rapidly and efficiently test the anti-migratory effects of many experimental conditions on cancer cell populations.The focus in this thesis lies in two specific aspects that are important in anti-migratory drug screening: tracking cells inside an in vitro 3D environment and doing so using unmarked cells.
Doctorat en Sciences de l'ingénieur
info:eu-repo/semantics/nonPublished
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Wyse, Meghan M. "CXCL12 Mediated Regulation of the Cytoskeletal Regulator mDia2 Formin Induces Amoeboid Conversions and Cellular Plasticity in Migrating Human Breast Carcinoma Cells". University of Toledo / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1404042854.
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Alamer, Maha Mohammed. "Cellular and molecular mechanisms of action of UV sunscreens in the regulation of growth and motility of human breast cancer cells". Thesis, University of Reading, 2016. http://centaur.reading.ac.uk/72239/.
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Breast cancer is a major health problem and exposure to oestrogen is a main risk factor. Many environmental chemicals with oestrogenic activity are known to enter the human breast from exposure through diet, the domestic environment and personal care products. In this study, six chemicals, used to absorb ultraviolet light (UV screens) in consumer products and known to be detectable in human milk, have been studied for their effects on proliferation and migration of MCF-7, T-47-D and MDA-MB-231 human breast cancer cells. The six chemicals were benzophenone-1 (Bp1), benzophenone-2 (Bp2), benzophenone-3 (Bp3), octylmethoxycinnamate (OMC), 3-(4-methylbenzilidene) camphor (4MBC) and homosalate (HS). All six of these UV screens at 10-5M could induce luciferase activity from an ERELUC reporter gene stably transfected into MCF-7 cells. Dose-response experiments on proliferation of oestrogen-responsive MCF-7 and T-47-D cells showed increased proliferation following the exposure to the UV screens but not OMC, which had no effect on proliferation of MCF-7 cells except when cells are seeded on a laminin matrix. No effect on MDA-MB- 231 cell proliferation was recorded. Although the oestrogenic activity of these chemicals has been shown to influence proliferation, this is only one of the hallmarks of cancer cells. Another important hallmark is activation of invasion and metastasis which is relevant for breast cancer where mortality arises not from growth of the primary tumour but from metastatic tumour spread. Effects of these UV screens have therefore been studied on migration and invasion of MCF-7, T-47-D and MDA-MB-231 cells following prior (2 weeks) or (up to 30 weeks) exposure using a wound healing assay, time-lapse microscopy or xCELLigence technology. 2 weeks of exposure to10-5M OMC, 4MBC and HS increased the motility of MCF-7 cells as determined by xCELLigence technology or time-lapse microscopy. 21 weeks of exposure to 10-5 M Bp1, Bp3, to 10-7M concentrations of OMC, 4MBC and HS increased the motility of MCF-7 cells. Results using western immunoblotting suggest a decrease in E-cadherin mRNA levels by 10-5 M Bp1, Bp3, OMC, 4MBS and HS and protein levels of cells exposed to 10-5 M Bp1 and HS.10-5M Bp1 also increased the secretion of MMP-9 as measured by zymography and the protein levels of pro-MMP-14 as measured by western immunoblotting. β-catenin protein was reduced in MCF-7 cells following the exposure to 10-5M OMC, which also reduced the mRNA levels of other two molecular markers of motility (PIK3R1 and BMP7). T-47-D cells exposed to 10-5M of the UV screens have shown an increase in motility as determined by xCELLigence but only Bp1 increased the migration as determined by wound healing. MDA-MB-231 cells showed no increase in motility following 2 weeks of exposure to the UV screens. However, 8 weeks of exposure to 10-7 M Bp2, Bp3, 4MBC and HS increased the cells motility as determined by the xCELLigence and 15 weeks of exposure to 10-7 M of the UV screens increased the motility of MDA-MB-231 cell as measured by the time-lapse microscopy. OMC and 4MBC increased the secretion of MMP-2 by MDA-MB-231 cells. Overall, these results demonstrate for the first time that these six UV screens can influence not only proliferation but also migration of human breast cancer cells.
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Subisak, Angel Dharshini. "Role of Substrate Stiffness on Migratory Properties and Epithelial to Mesenchymal Transition in Human Lung Cancer Cells". The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1356943256.
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Girault, Alban. "Inhibition du canal SK3 et du développement de métastases par un ether-lipide synthétique". Thesis, Tours, 2011. http://www.theses.fr/2011TOUR3305/document.
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Il a été mis en évidence que le canal SK3 est un médiateur de la migration de cellules cancéreuses mammaires, une propriété essentielle à la formation de métastases. Par ailleurs, ce canal est inhibé par l’édelfosine, un éther-lipide ayant des propriétés anti-tumorales in vitro mais son usage en clinique a été abandonné en raison d’effets secondaires. Une première partie de ce travail a permis de déterminer les parties de l’édelfosine nécessaires à l’inhibition du canal SK3 et de la migration cellulaire. Ceci nous a permis de sélectionner l’Ohmline (1-O-Hexadécyl-2-O-Méthyl-sn-glycéro-lactose), un analogue non toxique de l’édelfosine qui conserve son activité inhibitrice de SK3 et de la migration. Dans un deuxième temps, nous avons testé ce lipide dans un modèle murin de développement tumoral et nous avons montré qu’il réduisait le développement des métastases sans modifier la tumeur primaire. En conclusion, nous avons décrit l’Ohmline qui est le premier inhibiteur lipidique de SK3 et qui pourrait devenir le premier membre d’une famille de composés lipidiques inhibiteurs de la formation de métastasesIt has been shown that SK3 channel was a mediator of breast cancer cells migration, a fundamental property for metastasis formation. In addition, edelfosine inhibits SK3 channel. This ether-lipid owns a high anti cancerous potential in vitro but its clinical use was hampered by some side effects, Firstly, we showed the structural parts of edelfosine required for SK3 channel inhibition and cell motility inhibition. Moreover, we selected Ohmline (1-O-Hexadécyl-2-O-Méthyl-sn-glycéro-lactose), an edlefosine’s analogue that preserves SK3 channel and motility inhibitory properties. Secondly, we evaluated this lipid on tumor development in nude mice model. We showed that this lipid reduces metastasis formation without effect on primary tumor. To conclude, we described Ohmline, the first lipid inhibitor of SK3. This compound should become the first member of a new family of metastasis lipid inhibitors
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Sequin, Emily Katherine. "Effects of Induced Electric Fields on Tissues and Cells". The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1403869854.
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Tozluoglu, M. "Multiscale modelling of cancer cell motility". Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1383588/.
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Cell motility is required for many biological processes, including cancer metastasis. The molecular requirements for migration and, the morphology of migrating cells, can vary considerably depending on matrix geometry. Therefore, predicting the optimal migration strategy or the effect of experimental perturbation is difficult. This thesis presents a computational model of single cell motility that encompasses flexible cell morphology, actin polymerisation based protrusions, cell cortex asymmetry, plasma membrane blebbing, local cortex heterogeneity at the protein level, cell–extracellular matrix adhesion, and varying extracellular matrix geometries. This computational model is used to explore the theoretical requirements for rapid migration in different matrix geometries. The analysis reveals that confinement of the cell within the extracellular matrix brings profound changes in the relationship between cortical contractility and cell velocity. In confined environments with discontinuity, the relationship between adhesion and cell velocity is fundamentally altered: adhesion becomes dispensable for a large range of gap sizes in between the extracellular matrix filaments. The utility of the model is shown by predicting cancer cell behaviour in vivo, in terms of both cell velocity and the morphology of the motile cell. Furthermore, the model is challenged to predict the effects of selected biochemical perturbations that alter i) cortical contractility, ii) cell-ECM adhesion, and iii) signalling between the cell-ECM adhesion sites and intracellular regulators of cell motility machinery. Multiphoton intravital imaging is used to verify bleb driven migration of melanoma, breast cancer cells, and, surprisingly, endothelial cells at tumour margins. Intravital imaging of melanoma verified model predictions on cell velocity, cell morphology, nucleus behaviour, and effects of anti-invasive interventions. The model succesfully predicted melanoma velocities in vitro and in vivo. Moreover, it successfully predicted the effects of anti-invasive interventions, showing all perturbations will result in significant reduction in cell velocity in vitro, whereas only perturbation of cortical contractility will affect cell velocity in vivo. The model also successfully predicted the interactions of the cell nucleus with the cell cortex and the cell morphology upon intervensions. Overall, from measure ment of rather simple variables in vitro, the model has been able to predict the in vivo response of three very different putative anti-invasive interventions.
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Acton, S. E. "Mechanisms of cancer cell motility in vivo". Thesis, University College London (University of London), 2008. http://discovery.ucl.ac.uk/1387309/.
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Pinner, Sophie Elizabeth. "Mechanisms of cancer cell motility in vivo". Thesis, University College London (University of London), 2008. http://discovery.ucl.ac.uk/1444471/.
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This thesis describes investigations into mechanisms responsible for cancer cell motility in vivo. Chapters 1 and 2 provide a review of current literature in this field and also describe the techniques used to generate the following the results. Chapter 3 describes a candidate-based approach to investigate whether ROCK1 might be regulated by phosphorylation. Mutagenesis of ROCK1 was carried out at 3 chosen sites (T233 T380 T398) in the activation loop and the hydrophobic domain and the phenotypes of the mutants were analysed. Chapter 4 describes a parallel approach finding phosphorylation sites in ROCK1 by mass spectrometry. From these results T518 was chosen for further investigation and its possible function is investigated. Chapter 5 describes an siRNA screen designed to identify novel regulators of the cortical acto-myosin cytoskeleton. The read-out for this was based on the disruption of rounded blebbing morphology of A375 cells cultured on 3D gel matrices. The rounded morphology is similar to that observed in amoeboid cancer cell motility in vivo, therefore we hypothesised that genes required for contracted, rounded morphology might also be required for motility. Results identified PDK1 amongst other genes as a potential regulator of contractile forces in A375 cells and the role of PDK1 was investigated further. It was found that PDK1 was required both in vitro and in vivo for amoeboid cell motility. Chapters 6,7 and 8 detail the investigations into the mechanism of how PDK1 regulates the cytoskeleton and amoeboid cell motility. It was shown that PDK1 was responsible for the localisation of ROCK1 but not ROCK2 at the plasma membrane. This regulation was achieved by the direct binding of ROCK1 to PDK1. It was further found that PDK1 was able to compete with and prevent RhoE, a negative regulator of ROCK1, from binding. Chapter 9 investigates the relationship between cell morphology, motility and pigment production. It was found that it was possible to image melanin containing vesicles using multiphoton excitation, and using this technique, the motile behaviour of pigmented melanoma cells was observed in vivo. It was found that motile invasive cells tended to contain less melanin than non-motile cells suggesting that they were less well differentiated. This chapter details investigations into what differences in signalling could be responsible for a switch to a de-differentiated, more invasive/metastatic phenotype. The final chapter discusses the findings contained within this thesis and the possible implications.
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Bochenek, Magdalena Ludmila. "Regulation of cell motility by ephrin-B2 signalling". Thesis, University of Bristol, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.492474.
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Ephrin ligands and their Eph receptor tyrosine kinases both are surface tethered proteins that control cell shape and movements through direct cell-cell contact. Their binding, and subsequent clustering, triggers bidirectional signalling pathways, with signals transduced from the receptor (forward) and the ligand (reverse), that regulate the behaviour of both Eph- and ephrin- expressing cells. Recent evidence suggests that reverse ephrin-B2 signalling controls endothelial cell sprout outgrowth and tip elongation, and smooth muscle cell shape changes and behaviour. In addition, misregulation of ephrin-B2 expression is observed in various tumour types and high expression of this ligand is correlated with increased tumour vascularisation and tendency to metastasise. To investigate how ephrin-B2 "reverse" signalling pathways direct changes during angiogenesis and how the expression level of ephrin ligands influences changes in cell behaviour and cell mot motility, I have used Human Umbilical Vein Endothelial Cells (HUVECs) overexpressing ephrin ligands as a model system.
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Rucka, Marta. "Metabolic regulation of tumour cell motility". Thesis, University of Southampton, 2013. https://eprints.soton.ac.uk/380962/.
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Volakis, Leonithas I. "Effect of Myoferlin Depletion on Breast Cancer Cell Motility". The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1316453651.
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Scott, Rebecca Wilson. "LIM kinase regulation of cell motility and invasion". Thesis, University of Glasgow, 2010. http://theses.gla.ac.uk/2247/.
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This thesis describes how both LIM Kinase 1 and LIM Kinase 2 are both important regulators of cell invasion. Chapter 3 presents data that shows that inhibition of LIMK function blocks the collective invasion of MDA MB 231 breast carcinoma cells in a three-dimensional matrix. Although LIMK was not required for cell motility in two dimensions, a novel role for LIMK in both extracellular matrix degradation and deformation activities was shown in three dimensions in Chapter 4. Consistent with matrix remodeling being a requirement for path generation by leading cells in collective invasion, LIMK activity was also shown to be required by leading cells in MDA MB 231 collective invasion. However, it was also discovered that LIMK activity was not required for path following MDA MB 231. The importance of Cofilin activity as a conduit of LIMK activity during invasion was investigated in Chapter 5, a well as potential novel protein interactions of Cofilin. The identification of novel substrates of LIMK was attempted in Chapter 6, leaving prospective routes of investigation to further elucidate the roles of LIMK1 and LIMK2 in cells. The main findings presented in this thesis reveal a requirement for LIMK activity in the path generation function of leading cells in collective invasion. Given that individual invading cells must generate their own paths, these results lend support to the continued development of LIMK inhibitors to counter tumor cell invasion and metastasis.
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Aloliqi, Abdulaziz A. "The Role of Connexin 43 in Prostate Cancer Cell Motility". Kent State University / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=kent1556029596055296.
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Idoux-Gillet, Ysia. "Implication des voies de différenciation épithéliale précoce dans la morphogenèse mammaire et la progression des cancers du sein". Thesis, Montpellier 1, 2013. http://www.theses.fr/2013MON1T008.
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La morphogenèse de la glande mammaire résulte de la coordination de différentes voies, incluant l'apoptose, la prolifération, la différenciation et la dynamique des cellules souches/progénitrices. La transition épithéliale-mésenchymateuse (EMT) semble être impliquée dans ces voies de signalisation. Ainsi, nous nous sommes concentrés sur le facteur de transcription Slug, un gène clé régulant l'EMT, et son implication dans la morphogenèse de la glande mammaire. Dans un premier temps, en utilisant un modèle de souris transgéniques Slug-Lacz, nous avons localisé Slug dans une sous-population couvrant 10 à 20% des cellules basales du tubule et des cap cells du bourgeons terminal, coexprimant les marqueurs P-cadhérine, CK5, CD49f. Ensuite, nous avons montré par des expériences in vitro de perte et de gain de fonction, que Slug régulait la différenciation et la prolifération des cellules épithéliales mammaires. De plus, nous avons trouvé que Slug inhibait l'apoptose, promouvait la motilité cellulaire, et permettait l'émergence et la croissance de mammosphères clonales. Ce dernier point montre l'implication de Slug dans les cellules souches, qui est renforcé par le fait que des cellules primaires déficientes pour Slug étaient incapables de donner des mammosphères secondaires. Par ailleurs, nous avons pu observer in vivo que les souris déficientes pour Slug présentaient un retard de développement de la glande mammaire, possédant moins de cellules en prolifération, et une surexpression des marqueurs des cellules luminale CK8/18, GATA3 et ER. D'autres gènes régulant l'EMT sont retrouvés surexprimés, suggérant un mécanisme de compensation, qui peut expliquer le fait que le retard de développement de la glande mammaire est rattrapé à l'âge adulte. Les glandes mammaires Slug-knockout présentaient également des branchements excessifs, évoquant une différenciation précoce, similaire aux glandes mammaires de souris déficientes pour la P-cadhérine, exprimée dans les cellules basales. Sachant cela, nous avons constaté que la P-cadhérine était diminuée dans les glandes mammaires Slug-knockout, et dans les cellules CommaDβ traitées par siRNA ciblant Slug. Nous avons alors trouvé que Slug se liait directement au promoteur de la P-cadhérine et l'activait, et que cette dernière intervenait dans certains effets fonctionnels de Slug, tels que la croissance de mammosphères, la différenciation et la migration cellulaire. Ainsi, nous avons montré l'importance d'une nouvelle voie de signalisation Slug/P-cadhérine dans les capacités souches/progénitrices des cellules épithéliales mammaires, intégrant la différenciation et la motilité cellulaire, et nous avons maintenant une meilleure compréhension de son rôle dans l'agressivité de certains cancers du seinMammary gland morphogenesis results from the coordination of different pathways, including apoptosis, proliferation, differentiation, and stem/progenitor cell dynamics. Epithelial-mesenchymal transition (EMT) appears to be involved in these signalling pathways. Thus, we focused on transcription factor Slug, a key gene regulating EMT, and its involvement in mammary gland morphogenesis. First, using a Slug–LacZ transgenic mice model, we located Slug in a subpopulation covering about 10–20% basal duct cells and cap cells of terminal end bud, coexpressed with basal markers P-cadherin, CK5 and CD49f. Then, we have shown by in vitro experiments of loss and gain of function that Slug regulated the differentiation and proliferation of mammary epithelial cells. Moreover, we found that Slug inhibited apoptosis, promoted cell motility, and allowed the emergence and growth of clonal mammospheres. This last point shows the involvement of Slug in stem cells, which is reinforced by the fact that primary cells deficient for Slug were unable to give secondary mammospheres. Furthermore, we observed in vivo that mice deficient for Slug showed delayed development of the mammary gland, with less proliferating cells, and overexpression of markers of luminal cells CK8/18, GATA3 and ER. Other genes regulating EMT are found overexpressed, suggesting a compensatory mechanism, which can explain the fact that the delayed development of the mammary gland is caught up in adulthood. The Slug-knockout mammary glands also showed overbranching, evoking an early differentiation, similar to the mammary glands of mice deficient in P-cadherin, expressed in the basal cells. Knowing this, we found that P-cadherin was decreased in Slug-knockout mammary glands, and in CommaDβ cells treated with siRNA targeting Slug. We then found that Slug binds directly to the promoter of the P-cadherin and activated it, and that P-cadherin was involved in some functional effects of Slug, such as mammospheres growth, differentiation and cell migration. Thus, we have shown the importance of a new signalling pathway Slug/P-cadherin in the capacity of mammary epithelial stem/progenitor cells, integrating differentiation and cell motility, and we now have a better understanding of its role in the aggressiveness of some breast cancers
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Biondini, Marco. "RALlying through cell motility and invasion". Thesis, Paris 11, 2014. http://www.theses.fr/2014PA11T042.
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La formation des métastases est un processus en plusieurs étapes à travers lequel les cellules néoplasiques se détachent de la tumeur primaire pour constituer des tumeurs secondaires à distance. Les capacités à migrer et à envahir, des cellules tumorales sont cruciales dans la cascade métastatique. Selon le type cellulaire et les stimuli présents dans le microenvironnement tumoral, les cellules peuvent se déplacer collectivement ou individuellement selon un programme de migration mésenchymateuse ou amiboïde. Différentes voies de signalisation sont liées à la régulation de la motilité cellulaire. Les GTPases Rho (Rac1, Cdc42 et RhoA) contrôlent la migration en régulant la dynamique du cytosquelette d’actine, la contraction acto-myosine et les microtubules. Rac1 régule la motilité mésenchymateuse en favorisant la formation des lamellipodes via un complexe multiprotéique, le « Wave Regulatory Complex (WRC) » et RhoA contrôle la motilité amiboïde en favorisant la contraction du cytosquelette d'acto-myosine. Les protéines Ral (RalA et RalB) appartenant à une autre famille de petites G, ont été récemment impliquées dans la régulation de la migration cellulaire. RalB, à travers le complexe « Exocyst » joue un rôle essentiel dans la motilité. Dans ce travail de thèse, nous avons étudié les mécanismes moléculaires par lesquels la voie RalB/Exocyste contrôle la motilité et l'invasion cellulaire. La première partie de ce travail démontre que l’Exocyste interagit avec SH3BP1, une protéine GAP (GTPase Activating Protein) (projet 1). Nous montrons que l’interaction entre SH3BP1 et Rac1 est nécessaire à l’activité de Rac1 au front de migration. Dans le projet 2, nous montrons que l’Exocyste interagit directement avec WRC, ce qui est un élément clé de la polymérisation de l'actine. Cette interaction est nécessaire à la localisation du complexe WRC au front de migration où il contrôle la formation de protrusions membranaires. Dans de nombreux carcinomes, la transition épithélio-mésenchymateuse (EMT) joue un rôle important dans la promotion de la migration, l’invasion et la formation des métastases. Le projet 3 a permis de mieux caractériser la plasticité de migration et l’invasion des cellules cancéreuses post-EMT et d’étudier la contribution de Ral dans l'invasion des cellules post-EMT. Nous montrons qu’après l’EMT les cellules envahissent la matrice individuellement ? en utilisant la contraction du cytosquelette d'acto-myosine. Nous montrons que RalB est nécessaire à l’invasion des cellules post-EMT, et à la contractilité cellulaire. Nous proposons que le rôle de RalB dans l'invasion passe par GEF-H1 qui est une protéine GEF (Guanine Nucleotide Exchange Factor) de Rho associée à l’Exocyste. Dans la dernière partie de ce manuscrit, nous présentons le logiciel « AVeMap » que nous avons développé afin d’automatiser la quantification des paramètres de la migration cellulaire.En résumé, dans ce travail de thèse nous montrons que la voie Ral/Exocyste est un organisateur moléculaire nécessaire à l’exécution à la fois de la motilité cellulaire contrôlée par Rac1 et à la motilité contrôlée par RhoMetastasis is a multistep process by which cancer cells migrate away from the primary neoplastic mass to give rise to secondary tumors at distant sites. Thus, the acquisition of motility and invasive traits by tumor cells is a crucial step for metastasis to occur. Depending on the cell type and the environment, cells can move collectively keeping stable cell-cell contacts or as individual cells, which translocate by exploiting either mesenchymal or amoeboid motility programs.Different molecules and pathways have been linked to the regulation of cell motility. Rho small GTPases (Rac1, Cdc42 and RhoA) control cell migration through their actions on actin assembly, actomyosin contractility and microtubules. Rac1 drives mesenchymal-type motility by promoting lamellipodia formation via the Wave Regulator Complex (WRC). On the contrary, amoeboid motility is governed by RhoA which promotes cell movement via the generation of actomyosin contractile force. Another family of small GTPases, the Ral proteins, was recently involved in the regulation of cell migration. RalB, through the mobilization of its main effector the Exocyst complex, was shown to play an essential role in cell motility. In this work of thesis we investigated the molecular mechanisms through which RalB/Exocyst pathway controls cell motility and invasion.In the first part of this manuscript we show that Exocyst interacts with the RacGAP SH3BP1 (project 1). In mesenchymal moving cells Exocyst/SH3BP1 interaction is required to organize membrane protrusion formation by spatially regulating the activity of Rac1 at the cellular front. In addition, in project 2, we show that the Exocyst binds to the wave regulator complex (WRC), a key promoter of actin polymerization. We provide evidences for Exocyst to be involved in driving the WRC to the leading edge of motile cells, where it can stimulate actin polymerization and membrane protrusions. Reactivation of a developmental program termed epithelial-mesenchymal transition (EMT) was recently shown to promote motility, invasion and metastasis of neoplastic cells. Tumor cells undergoing EMT loose cell-cell contacts acquire a fibroblastoid phenotype and invade the surrounding tissues as individual cells. In project 3 we characterized the invasion plasticity of cancer cells after EMT and we investigated the molecular contribution of Ral to post-EMT invasion. We showed that upon EMT cells disseminate individually in a Rho-driven fashion exploiting the generation of actomyosin force to deform the extracellular matrix. We document that RalB silencing severely impairs actomyosin contractility and dissemination of post-EMT cells. We hypothesize that RalB regulates invasion by controlling the dynamics of the Rho pathway via the Exocyst-associated RhoGEF GEF-H1 in post-EMT cells. Finally, in the last part of this thesis manuscript, we present the PIV-based “AVeMap” software which has been developed to quantify in a fully automated way cell migration and its parameters (Project 4).Taken together the results presented in this thesis manuscript point out the Ral/Exocyst pathway as a key molecular organizer of the execution of both Rac1- and Rho-driven motility programs
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Sengupta, Sameer. "The influence of BRCA1's ubiquitin ligase activity on cell motility". Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:b14af4ae-1f95-4d0c-85a8-faaf4fa950c4.
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Breast cancer type 1 susceptibility protein (BRCA1) has been established as an important tumour suppressor protein and its loss of function is associated with hereditary breast and ovarian cancer. An emerging body of work suggests that BRCA1 is involved in sporadic cases of breast and ovarian cancers and may also have a role in other cancers, indicating a more global role in tumourigenesis. BRCA1-mutated cancers can be early-onset and are characterised by being highly aggressive with a propensity to metastasize, thus from a clinical perspective there is a requirement to understand the molecular mechanisms in order to be able to tailor treatments and develop therapeutics. BRCA1 has numerous cellular functions, many ascribed to its role in maintenance of genome integrity, transcription and checkpoint control. More recently, a number of extra-nuclear roles have been established. An interesting novel function is the role of the E3 ubiquitin ligase activity on cell motility. Abrogation of the ubiquitin ligase activity of BRCA1 results in cells exhibiting a hypermotile, invasive phenotype which may help to account for the metastatic nature of BRCA1-mutated tumours. Our aim was to further elucidate BRCA1’s role in cell motility, starting with the identification of relevant candidate ubiquitin ligase substrates. To date, there has yet to be a systematic approach to identify BRCA1’s ubiquitin ligase substrates. Thus we undertook an unbiased proteomic approach to identify extra-nuclear candidates by comparing the profiles of ubiquitinated proteins in breast cancer epithelial cells expressing either functional BRCA1 or ubiquitin ligase-dead BRCA1. We identified 55 candidates which were differentially enriched between the two cell lines and through pathway analysis we determined a significant proportion were cytoskeletal and translation related proteins. Using an ubiquitin-remnant profiling approach, we also identified the site(s) of ubiquitination for many of the candidates. To assess the role of these candidates in cell motility initially we adopted an in silico approach. We used existing time-lapse movies from the online database (www.mitocheck.org) which systematically siRNA knocked down every single gene in the human genome. We developed a series of algorithms which track cell motility from these movies and used these to analyse 192,000 movies containing 3.5 billion cell steps. We have produced a complete database containing motility information after siRNA knockdown of every gene in the human genome, which has been annotated with gene ontologies, KEGG families, Gene Descriptions, SwissProt, Ensembl IDs and siRNA information. In addition to providing motility data of our candidates, we also carried out gene set enrichment analysis on the whole dataset to uncover structural or functional families that may be involved in up-regulating motility when knocked down by siRNA. This is the first report of a genome-wide motility database. Based on overlaps between the results from these two large-scale unbiased proteomic and in silico datasets, we selected 4 candidates, namely, ezrin, moesin, fermitin-2 and delta-catenin. Through monolayer wound healing, cell spreading and single cell motility assays, we determined that ezrin was a particularly relevant and informative candidate. The hypermotile phenotype observed in cells expressing ubiquitin ligase dead BRCA1 was rescued through siRNA knockdown of ezrin and thus we suggest that BRCA1 may regulate cell motility through effects on ezrin. This thesis has investigated candidate BRCA1’s role in cell motility, identified candidate substrates for the E3 ubiquitin ligase activity, established a genome-wide motility database and proposed a possible pathway through which BRCA1 may mediate cell motility and by extension metastasis.
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Zago, Giulia. "Lighting up Invasion with Optogenetics : RalB Mobilizes the WRC Complex Downstream Ras". Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS333.
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La formation des métastases est un processus multi étapes à travers lequel les cellules cancéreuses se détachent de la tumeur primaire pour envahir à distance dans un site secondaire. L’acquisition de capacités migratoires et invasives des cellules tumorales est cruciale dans la cascade métastatique. L'activation mutationnelle des protéines Ras favorise l'oncogenèse en perturbant une multitude de molécules et de voies qui sont impliquées dans la régulation de plusieurs processus, y compris l'invasion cellulaire et la motilité. Les petites Rho GTPases (Rac1, Cdc42 et RhoA)jouent un rôle central en contrôlant la migration cellulaire via l'assemblage des fibres d'actine, la contractilité de l'actomyosine et des microtubules.Rac1 stimule la motilité de type mésenchymateuse en favorisant la formation de lamellipodes via la formation du complexe régulateur Wave(WRC), un promoteur clé de la polymérisation de l'actine. Les protéines Ral,une autre famille de petites GTPases agissant en aval de Ras, a récemment été impliquée dans la régulation de la migration cellulaire. En particulier,RalB joue un rôle essentiel dans la motilité cellulaire en mobilisant le complexe Exocyst, son principal effecteur. Durant mon projet de thèse,nous avons investigué les mécanismes moléculaires qui contrôlent la motilité cellulaire et l'invasion en aval de la voie oncogénique Ras via le complexe RalB / Exocyst.Dans la première partie de ce manuscrit, nous avons identifié et caractérisé que le complexe WRC est à la fois un nouveau partenaire et mais aussi acteur du complexe Exocyst. En outre, nous démontrons que le complexe Exocyst dirige le complexe WRC à l’extrémité des cellules4mobiles. Cette hypothèse a été caractérisée dans la deuxième partie du manuscrit. En effet, en utilisant la technique d’optogénétique nous avonsmis en évidence le mécanisme moléculaire impliqué dans l'invasion.L’activation de RalB par Ras via les facteurs d'échange Rgl1 et Rgl2,mobilise le complexe Exocyst qui recrute ainsi le complexe WRC à l’extrémité des cellules. Cette cascade d’activation favorise la formation de protrusions, la migration et l'invasion. De manière surprenante, nous montrons que la GTPase Rac1, considérée comme la GTPase clée dans la formation de protrusions cellulaires, n'est pas impliquée dans ce processus.Enfin, nous avons analysé le niveau des protéines Ral dans une cohorte de patientes atteintes de cancer du sein. Nos résultats montrent pour la première fois une accumulation de la protéine RalB dans les compartemets invasif et métastatique suggérant un rôle potentiel de RalB dans l'invasion et la propagation métastatique des cancers du sein humain. Pour conclure,notre travail met en évidence un rôle crucial de la voie Ral, souvent sousestimée,dans le contexte de l'invasion cancéreuseMetastasis is a multistep process by which cancer cells migrate awayfrom the primary neoplastic mass to give rise to secondary tumors at distantsites. Thus, the acquisition of motility and invasive traits by tumor cells is acrucial step for metastasis to occur. Mutational activation of Ras proteinspromotes oncogenesis by disturbing a multitude of molecules andpathways that participate to the regulation of several processes includingalso cell invasion and motility. Among them a central role is played by Rhosmall GTPases (Rac1, Cdc42 and RhoA) which control cell migrationthrough their actions on actin assembly, actomyosin contractility andmicrotubules. Rac1 drives mesenchymal-type motility by promotinglamellipodia formation via the Wave Regulator Complex (WRC), a keypromoter of actin polymerization. Another family of small GTPases that actdownstream Ras, the Ral proteins, has been recently involved in theregulation of cell migration. RalB, through the mobilization of its maineffector the Exocyst complex, was shown to play an essential role in cellmotility. In this work of thesis, we investigated the molecular mechanismsthrough which RalB/Exocyst pathway controls cell motility and invasiondownstream oncogenic Ras.In the first part of this manuscript we describe the identification andcharacterization of the WRC complex as a novel interactor of the Exocyst.Furthermore, we provide evidences for Exocyst to be involved in drivingthe WRC to the leading edge of motile cells. This hypothesis, was finallydemonstrated in the second part of the manuscript. We were able to definethe mechanisms underlying the function of RalB in invasion by exploitingan optogenetic approach. We found that RalB, activated by Ras via the2Rgl1 and Rgl2 exchange factors, mobilizes the Exocyst complex whichrecruits the Wave Regulatory Complex (WRC) at cell edge, promotingprotrusions, migration and invasion. Even more, we show that the Rac1GTPase, usually considered the master of cell protrusions, is not involvedin this process. Finally, we analyzed Ral proteins expression in a cohort ofbreast cancer samples, pointing out for the first time an accumulation ofRalB in the invasive and metastasis compartments, suggesting a role ofRalB in invasiveness and metastatic spread of human breast cancers. Takentogether our work contribute to light up the role of the underestimated Ralpathway in the context of cancer invasion
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Zhang, Yang. "A dynamical systems modelling framework for breast cancer cell motility and morphology analysis". Thesis, University of Sheffield, 2017. http://etheses.whiterose.ac.uk/16014/.
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Cancer is a worldwide disease and, in the UK, breast cancer is the most common. Compared to healthy cells, cancer cells migrate abnormally, associated with alterations in cell motility and morphology. The development of biomedical imaging techniques result in the production of large amounts of data. The analysis of such large data, the variety of cancer cell shapes and the potential links between cell motility and morphology present a challenge for cell migration study: how to analyse cell motility and morphology simultaneously. This thesis proposes a computational framework to address integrated cancer cell migration analysis. Firstly, automated tracking of cell boundaries is undertaken by a DWNA kinematic model of cell boundaries, described by B-spline active contours. The tracked cell states intrinsically links cell morphology to motility features. As a result, cell centroid and boundary dynamics are successfully tracked, followed by quantitative motility analysis. A module to quantitatively analyse cell morphology is proposed after tracking. Cell shapes are described by a 2D descriptor. Accordingly, cell morphodynamics are modelled as a hidden Markov process, along with three shape states: round, elongated and teardrop. In order to explore the potential interactions between cell shapes and motility, cell centroid motility characteristics are associated to the identified shape states. When the analysis was applied to breast cancer control cells, the identified shape states showed distinct motility characteristics. Finally, the proposed framework is adapted to the comparison of MDA-MB-231 cell behaviours with regulating migration-associated proteins: i) Blebbistatin and Y-27632, which are chemical inhibitors of two different proteins working on the same pathway, showed identical, but different degrees of effects on the motility and morphology characteristics of MDA-MB-231 cells. ii) The absence of FA-associated genes, including FAK, RhoE and beta-PIX, respectively showed distinct effects on cell migrations.
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Munro, Catriona. "Novel target identification & characterisation of key cell motility regulators in lung cancer metastasis". Thesis, Imperial College London, 2014. http://hdl.handle.net/10044/1/24741.
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Lung cancer is the most common cancer killer worldwide. One of the major reasons for failing to cure this malignancy is the high rate of metastasis. Hence, understanding the mechanisms by which these cells metastasise is required to improve patients' survival. Using the non-small cell lung cancer cell line A549 we optimised a 3D Invasion assay to enable a robotised high-throughput siRNA screen of large gene libraries. Despite thorough optimisation a pilot screen for the Phosphatome highlighted multiple issues with our set-up. Further optimisation work was conducted to improve the resolving power of the assay. However, as no clear explanation for the poor reproducibility could be uncovered, work began on a potential modulator of cell motility identified during a previous motility screen of the kinome. Microtubule affinity regulating kinases 4 (MARK4) is one of four members of the MARK family. A previously performed kinome siRNA screen for modulators of cell migration revealed that depletion of MARK4 reduced A549 cell migration. We validated this observation and additionally found that MARK4 silencing inhibited cell invasion through 3D collagen matrices. MARK4 depletion markedly changed cell structure, as exemplified by an increase tubulin network area. Follow-on experiments revealed an altered speed of microtubule polymerisation in MARK4-silenced cells. We observed that MARK4 downregulation promoted resistance to the chemotherapeutic agents Paciltaxel and Cisplatin, an effect potentially linked to a reduced proliferation in MARK4-silenced cells. MARK4 overexpression in NSCLC cells increased cell motility but did not impact the cell area or resistance to chemotherapy. A targeted siRNA cell motility screen of a selection of proposed MARK4 interacting proteins enabled us to connect MARK4 with Protein Phosphatase 2A and GSK3. Although further investigation is required into the signalling pathways upstream and downstream of MARK4, this work identified novel functions for this kinase and highlighted potential mechanisms underlying its effects.
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McCarty, Samantha Keiko. "A NOVEL BRAF SIGNALING CASCADE THROUGH p-21 ACTIVATED KINASES REGULATES THYROID CANCER CELL MOTILITY". The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1366201525.
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Buttermore, Stephanie T. "The Role of Elevated Hyaluronan-Mediated Motility Receptor (RHAMM/HMMR) in Ovarian Cancer". Scholar Commons, 2017. http://scholarcommons.usf.edu/etd/6808.
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Ovarian cancer (OC) has the highest mortality among gynecological cancers. The high mortality is associated with the lack of an accurate screening tool to detect disease in early stage. As a result the majority of OCs are diagnosed in late stage. Further, the molecular events responsible for malignant transformation in the ovary remain poorly understood. Consequently, delineating key molecular players driving OC could help elucidate potential diagnostic, prognostic and therapeutic targets.
Receptor for hyaluronan-mediated motility (RHAMM) belongs to a group of hyaladherins, which share a common ability to bind to hyaluronan (HA). Intracellularly, RHAMM is involved in microtubule spindle assembly contributing to cell cycle progression. On the cell surface, loosely tethered RHAMM forms a complex with cluster differentiation 44 and HA to activate cell signaling pathways that promote cellular migration, invasion and proliferation. Since RHAMM is overexpressed in a number of cancer types and it is often associated with an aggressive cancer phenotype, I sought to determine if RHAMM similarly contributes to OC.
I found that RHAMM is overexpressed in clinical specimens of OC by immuno-histochemistry and although both primary and metastatic OCs stain equally for RHAMM, RHAMM staining was most intense among clinically aggressive OC histologic subtypes. Further, using an in vitro model system, I was able to show that OC cells express and secrete RHAMM. Abrogation of RHAMM using silencing RNA technology inhibited OC cell migration and invasion suggesting that RHAMM may contribute, at least in part, to the metastatic propensity of OC.
Since RHAMM lacks an export signal peptide sequence and has not been reported to employ alternate mechanisms for extracellular secretion, I utilized computational analyses to predict post-translational glycosylation events as a novel mode for RHAMM secretion. N- glycosylation inhibitors abrogated RHAMM secretion by OC cells in vitro validating my prediction and identify a novel and potentially unconventional mode for RHAMM secretion.
Lastly, since RHAMM is secreted by OC cells, I sought to determine whether RHAMM could be detected in bodily fluids. In a pilot study, I found that urinary levels of RHAMM are elevated in OC patients as measured by enzyme-linked immunosorbant assays. Decreased urinary RHAMM levels noted following cytoreductive surgery support OC as the source of elevated urinary RHAMM levels. Finally, while obesity was associated with high urinary RHAMM levels in OC patients, combined measurements of urinary RHAMM and serum CA125 improved prediction of OC.
Taken together, the studies described herein suggest that RHAMM contributes to OC and that further studies are warranted to further elucidate the clinical role of RHAMM in OC.
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Shah, Nirav. "A novel link between Akt1 and Twist1 in ovarian tumor cell motility and invasiveness". Master's thesis, University of Central Florida, 2012. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/5490.
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Ovarian cancer results in more deaths per year than any other cancer of the female reproductive system. The low survival rate is partly due to the lack of early detection and the susceptibility to relapse. The AKT serine threonine kinase plays a pivotal role in hallmark cellular processes for the progression of ovarian cancer, including tumor cell growth and migration. Therapeutic targeting of pan-AKT has been problematic, in part due to feedback mechanisms and crosstalk with other pathways. The hypothesis for this study is that AKT 1, -2 and -3 isoforms may have different roles and regulate cell processes in uniquely varied ways. A transgenic mouse model that expresses the SV40 T-antigen viral oncogene and is known to have dramatically increased susceptibility to ovarian cancer was utilized, and it had genetic inactivation of either AKT1 or AKT2 through targeted deletion of the individual genes because these isoforms have been implicated in this cancer. Primary ovarian tumor cell cultures were established and found to exhibit different morphology, proliferation and migration that may indicate a different role for the AKT1 and AKT2 isoforms in these contexts. Ovarian tumor cells with absence of AKT1 predominantly exhibited reduced cell migration when compared to cells with retention of AKT1 and absence of AKT2. Since AKT is known to be important for epithelial-mesenchymal transition (EMT), a process potentially associated with tumor cell metastasis, the expression of transcription factors implicated in EMT was assessed by real-time array analysis in ovarian tumor cells knocked-out for either AKT1 or AKT2. Twist1, one of the major players in EMT, was not detectable in the cells missing the AKT1 isoform. Results indicate an association of Twist1 with AKT1 in EMT and migration of ovarian tumors cells. This finding is significant because AKT2 has been implicated as the major player of cell migration in human breast cancer cells. Collectively, these findings support a tissue specific role of the AKT isoforms, and may provide insights regarding the most useful cell context in order to target components of the AKT signaling pathway indirectly affecting EMT in order to prevent tumor progression in patients with ovarian and perhaps other types of cancers.M.S.
Masters
Molecular Biology and Micro
Medicine
Biotechnology
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Flate, Elizabeth L. "THE EFFECT OF EXTRACELLULAR MATRIX COMPONENTS ON MOTILITY AND CHEMOSENSITIVITY OF SELECT OVARIAN CANCER CELL LINES". Kent State University / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=kent1353954902.
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Hammer, Alan D. "Prolactin-Induced Tyrosyl Phosphorylation of PAK1 in Breast Cancer Cell Motility, Adhesion, and Epithelial-to-Mesenchymal Transition". University of Toledo / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1461066955.
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Foster, Clare Ruth. "A proteomic and genomic investigation into the role of lamin A in colorectal cancer cell motility". Thesis, Durham University, 2012. http://etheses.dur.ac.uk/3434/.
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Lamins are type V intermediate filament proteins found at the nuclear envelope. Expression of lamin A in colorectal cancer (CRC) tumours is correlated with poor prognosis and expression of lamin A in CRC cell lines promotes greatly increased cell motility. The aim of this study was to identify proteins that promote cell motility in response to lamin A expression and to investigate lamin A regulated changes in gene/protein expression and cytoskeletal organisation that might underpin the increased cell motility. The effects of lamin A expression were studied using quantitative proteomic and genomic methods using cells from the colorectal cancer cell line SW480 which had been transfected with GFP-lamin A (SW480/lamA) or GFP as a control (SW480/cntl). A biochemical fractionation technique was optimised for the preparation of cytoskeletal fractions which were analysed by 2D DIGE (2D difference in-gel electrophoresis) to reveal accurate and reproducible changes in the representation of proteins within the cytoskeleton in SW480/lamA cells compared to controls. The majority of proteins identified were either components of the actin/intermediate filament cytoskeleton, protein chaperones or translation initiation/elongation factors. Interestingly, tissue transglutaminase 2, a protein which modifies elements of the cytoskeleton and is associated with cancer progression, was highly over-represented in the cytoskeleton fraction of SW480/lamA cells. Ingenuity Pathway Analysis was used to analyse genome-wide Affymetrix microarray analysis of SW480/cntl and SW480/lamA cell lines. A highly significant interaction network was identified which clustered together genes linked to cancer, cellular movement and cellular growth and proliferation. Epithelial markers such as CDH1 were down-regulated and mesenchymal markers such as FN1 were up-regulated in cells expressing GFP-lamin A, which suggested that lamin A over-expression may lead to an epithelial-mesenchymal transition (EMT). As A-type lamins are known to modulate downstream effects of TGFβ signalling, and TGFβ is an inducer of EMT, changes in genes involved in TGFβ signalling were investigated. Knockdown of lamin A using siRNA led to decreased expression of TGFBI and SNAI2 followed by reduced cell motility. The data suggest that expression of lamin A in CRC cells causes changes in the organisation of the actin cytoskeleton and in TGFβ signalling, potentially involving an epithelial to mesenchymal transition, leading to increased cell motility and an increased risk of death from cancer.
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Brunel, Benjamin. "Mesure des déplacements cellulaires dans les tissus non transparents : une application de la diffusion dynamique de la lumière". Thesis, Université Grenoble Alpes (ComUE), 2018. http://www.theses.fr/2018GREAY047/document.
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Lorsqu'une tumeur grossit, elle exerce une pression sur les tissus environnants et est comprimée en retour. Des expériences sur un modèle de tumeur in vitro, appelé sphéroïde, ont montré que cette pression influence largement le devenir du tissu cancéreux, notamment en freinant sa croissance, mais aussi en le rendant plus invasif. Pour mieux comprendre ce dernier effet, nous avons cherché à étudier le comportement migratoire des cellules à l'intérieur d'un sphéroïde sous pression. Observer l'intérieur d'un sphéroïde pose cependant un problème technique car les méthodes usuelles d'imagerie ne sont pas utilisables dans des tissus épais (> 100 μm). L'imagerie classique étant limitée en profondeur à cause de la diffusion de la lumière, nous nous sommes tournés vers une méthode qui utilise justement celle-ci : la diffusion dynamique de lumière ou DLS (Dynamic Light Scattering). Nous avons développé son application à la migration cellulaire, afin d'obtenir la distribution des déplacements relatifs des cellules au cours du temps. Cette mesure est faite sans utiliser de marqueurs spécifiques et est applicable à des sphéroïdes allant jusqu'à 400 μm de diamètre. Nous avons ainsi mis en évidence une organisation radiale du sphéroïde en termes de mobilité, avec des cellules rapides en surface et plus lentes au centre. Nous avons aussi montré qu'en appliquant une contrainte au sphéroïde, la vitesse moyenne diminue jusqu'à être réduite de moitié pour des pressions supérieures à 15kPa. Une autre équipe a mesuré par ailleurs une augmentation de la vitesse des cellules en surface suite à une compression, ce qui indique que l'organisation radiale se retrouve dans la réponse à la pression. Nous avons montré que cette sensibilité à la pression est une propriété qui émerge de l'organisation 3D du tissu, dans laquelle la matrice extracellulaire joue un rôle primordial. Enfin, pour explorer les possibilités qu'offre notre technique, nous l'avons appliquée à une autre question : comment la migration des macrophages est-elle affectée par les signaux provenant de cellules apoptotiques ? Les résultats ont montré que les cellules apoptotiques précoces augmentent la vitesse des macrophages tandis que les cellules apoptotiques tardives la réduisent. D'un cas à l'autre, la longueur de persistance du mouvement est conservéeAs a tumor grows, it exerts a mechanical pressure on its surrounding tissue and is compressed back as a reaction. Recent experiments on an in vitro tumor model, called spheroid, have shown that this pressure is crucial for the fate of the cancerous tissue. In particular, the pressure slows down its growth, but makes it more invasive. To further understand the latter effect, we decided to study the migration of cells inside spheroids under pressure. However, imaging the inside of a spheroid is technically challenging as usual microscopy methods do not work on thick tissues (> 100 μm). Standard imaging methods are limited in terms of depth penetration because of light scattering. For this reason, we decided to take advantage of this scattered light with a method called Dynamic Light Scattering (DLS). We developed its application to cell migration in order to measure the distribution of cells displacements over time. The measurement is label-free and works with spheroids as thick as 400 μm in diameter. By this means, we revealed a radial organization inside the spheroid in terms of mobility, with fast cells at the surface and slower cells in the core. We also showed that applying a pressure onto spheroids decreases the average cell speed by a factor up to two for pressure greater than 15 kPa. Another team reported an increase in the speed of cells located at the surface of a compressed spheroid, which implies that the radial organization is also true for the impact of pressure. We demonstrated that this sensitivity to an external pressure is a 3D emergent property, in which the extracellular matrix plays an essential role. Finally, we explored the potential of our technique by addressing another question: how do apoptotic cells signals affect the migration of macrophages? We found that early apoptotic cells increase the speed of macrophages whereas late apoptotic cells decrease it. In both cases, the persistence length of the motion is the same
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Brown, Louise E. "Role of human Desmoglein 3 in the regulation of cell morphology and motility via AP-1 and PKC dependent Ezrin activation". Thesis, Queen Mary, University of London, 2014. http://qmro.qmul.ac.uk/xmlui/handle/123456789/26964.
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Desmoglein 3 (Dsg3) belongs to the desmoglein subfamily and functions as an adhesion molecule in desmosomes. Two pools of Dsg3 have been identified, detergent soluble and insoluble proteins. Recent studies show that DSG3 is upregulated in squamous cell carcinoma (SCC). However, its biological function in cancer remains poorly understood. The aim of this study was to investigate the extra-junctional functions of Dsg3, in particular its roles in signalling that regulates cell morphology and locomotion in cancer cells. This study adopted a unique cancer cell model with Dsg3 gain-of-function and has discovered two novel regulatory signal pathways that may play a crucial role in the control of cell invasion and metastasis in Dsg3 associated cancers. Firstly, Dsg3 regulates the phosphorylation of Ezrin at Thr567 in a PKCdependent manner that is crucial for its activation and regulation of actin based membrane projections and accelerated cell locomotion in SCC. Secondly, Dsg3 modulates the transcriptional activity of cJun:AP1 that is responsible for regulating a cohort of genes to confer an invasive phenotype. It is likely that these two pathways are closely linked in that the Dsg3-mediated activation of cJun:AP1 elicits PKCdependent Ezrin activation that in turn enable it to form a complex with Dsg3 at the plasma membrane to promote membrane projection and cell locomotion. Several lines of evidence support these conclusions: Dsg3 forms a complex with Ezrin at the plasma membrane and induces phosphorylation of Ezrin resulting in augmented membrane protrusions and cell migration. Dsg3 silencing inhibits junction formation concomitant with collapse of membrane protrusion. Furthermore, Dsg3 regulates the activity of cJun:AP1. Collectively, these findings provide new insight regarding Dsg3 in cancer, suggesting it acts as a key regulator of cell invasion and metastasis in SCC. Therefore, targeting Dsg3 could be a potential new strategy in the control of cancer progression and metastasis.
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Stevens, Payton D. "THE FUNCTION OF ERBIN, A SCAFFOLD PROTEIN, AS A TUMOR SUPPRESSOR IN COLON CANCER". UKnowledge, 2018. https://uknowledge.uky.edu/biochem_etds/36.
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Erbin belongs to the LAP (leucine-rich repeat and PDZ domain) family of scaffolding proteins that play important roles in orchestrating cell signaling. Here, we show that Erbin functions as a tumor suppressor in colon cancer. Analysis of Erbin expression in patient specimens reveals that Erbin is downregulated at both mRNA and protein levels in tumor tissues. Functionally, knockdown of Erbin disrupts epithelial cell polarity and increases cell proliferation in 3D culture. In addition, silencing Erbin results in an increase in the amplitude and duration of signaling through Akt and RAS/RAF pathways. Moreover, Erbin-loss induces epithelial-mesenchymal transition (EMT), which coincides with a significant increase in cell migration and invasion. Erbin interacts with KSR1 and displaces it from the RAF/MEK/ERK complex to prevent signaling propagation. Furthermore, genetic deletion of Erbin in Apc knockout mice promotes tumorigenesis and significantly reduces survival. Tumor organoids derived from Erbin/Apc double knockout mice have increased tumor initiation potential along with increased Wnt target gene expression as seen by qPCR. Collectively, the studies within this dissertation identify Erbin as a negative regulator of EMT and tumor progression by directly suppressing Akt and RAS/RAF signaling in vivo.
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Takahashi, Ryo. "AFAP1L1, a novel associating partner with vinculin, modulates cellular morphology and motility, and promotes the progression of colorectal cancers". Kyoto University, 2014. http://hdl.handle.net/2433/189659.
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Noll, Bettina [Verfasser], i Monilola [Akademischer Betreuer] Olayioye. "Isoform specific functions of protein kinase D3 (PKD3) in breast cancer cell proliferation and motility / Bettina Noll. Betreuer: Monilola Olayioye". Stuttgart : Universitätsbibliothek der Universität Stuttgart, 2014. http://d-nb.info/105253158X/34.
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Woo, Ho-Hyung, Csaba Laszlo, Stephen Greco i Setsuko Chambers. "Regulation of colony stimulating factor-1 expression and ovarian cancer cell behavior in vitro by miR-128 and miR-152". BioMed Central, 2012. http://hdl.handle.net/10150/610206.
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BACKGROUND:Colony stimulating factor-1 (CSF-1) plays an important role in ovarian cancer biology and as a prognostic factor in ovarian cancer. Elevated levels of CSF-1 promote progression of ovarian cancer, by binding to CSF-1R (the tyrosine kinase receptor encoded by c-fms proto-oncogene).Post-transcriptional regulation of CSF-1 mRNA by its 3' untranslated region (3'UTR) has been studied previously. Several cis-acting elements in 3'UTR are involved in post-transcriptional regulation of CSF-1 mRNA. These include conserved protein-binding motifs as well as miRNA targets. miRNAs are 21-23nt single strand RNA which bind the complementary sequences in mRNAs, suppressing translation and enhancing mRNA degradation.RESULTS:In this report, we investigate the effect of miRNAs on post-transcriptional regulation of CSF-1 mRNA in human ovarian cancer. Bioinformatics analysis predicts at least 14 miRNAs targeting CSF-1 mRNA 3'UTR. By mutations in putative miRNA targets in CSF-1 mRNA 3'UTR, we identified a common target for both miR-128 and miR-152. We have also found that both miR-128 and miR-152 down-regulate CSF-1 mRNA and protein expression in ovarian cancer cells leading to decreased cell motility and adhesion in vitro, two major aspects of the metastatic potential of cancer cells.CONCLUSION:The major CSF-1 mRNA 3'UTR contains a common miRNA target which is involved in post-transcriptional regulation of CSF-1. Our results provide the evidence for a mechanism by which miR-128 and miR-152 down-regulate CSF-1, an important regulator of ovarian cancer.
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Dayal, Shubham. "Novel Roles of RNase L in Prostate Cancer". University of Toledo / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1492793747213566.
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DeLigio, James T., i James Thomas DeLigio. "ALTERNATIVE SPLICING OF CYTOPLASMIC POLYADENYLATION ELEMENT BINDING PROTEIN 2 IS MODULATED VIA SERINE ARGININE SPLICING FACTOR 3 IN CANCER METASTASIS". VCU Scholars Compass, 2018. https://scholarscompass.vcu.edu/etd/5660.
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Our laboratory delineated a role for alternative pre-mRNA splicing (AS) in triple negative breast cancer (TNBC). We found the translational regulator cytosolic polyadenylation element binding protein 2 (CPEB2) which has two isoforms, CPEB2A and CPEB2B, is alternatively spliced during acquisition of anoikis resistance (AnR) and metastasis. The splicing event which determines the CPEB2 isoform is via inclusion/ exclusion of exon four in the mature mRNA transcript. The loss of CPEB2A with a concomitant increase in CPEB2B is required for TNBC cells to metastasize in vivo. We examined RNAseq profiles of TNBC cells which had CPEB2 isoforms specifically downregulated to examine the mechanism by which CPEB2 isoforms mediate opposing effects on cancer-related phenotypes. Downregulation of the CPEB2B isoform inhibited pathways driving the epithelial-to-mesenchymal transition (EMT) and hypoxic response, whereas downregulation of the CPEB2A isoform did not have this effect. Specifically, CPEB2B functioned as a translational activator of TWIST1 and HIF1a. Functional studies showed that specific downregulation of either HIF1α or TWIST1 inhibited the ability of CPEB2B to induce AnR and drive metastasis. The mechanism governing inclusion/ exclusion of exon 4 was determined to be serine/ arginine-rich splicing factor 3 (SRSF3). Binding of SRSF3 to a consensus sequence within CPEB2 exon 4 promoted its inclusion in the mature mRNA, and mutation of this sequence abolished association of SRSF3 with exon 4. SRSF3 expression was upregulated in TNBC cells upon acquisition of AnR correlating with a reduction in the CPEB2A/B ratio. Importantly, downregulation of SRSF3 by siRNA in these cells induced the exclusion of exon 4. Downregulation of SRSF3 also reversed the CPEB2A/B ratio in a wild-type CPEB2 exon 4 minigene construct, but not a mutant CPEB2 minigene with the SRSF3 RNA cis-element ablated. Physiologic studies demonstrated SRSF3 downregulation ablated AnR in TNBC cells, and was “rescued” by ectopic expression of CPEB2B. Importantly, biostatistical analysis of The Cancer Genome Atlas database showed a positive relationship between alterations in SRSF3 expression and lower overall survival in TNBC. Overall, this study demonstrates that SRSF3 modulates CPEB2 AS to induce the expression of the CPEB2B isoform that drives TNBC phenotypes correlating with aggressive human breast cancer.
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Gueguinou, Maxime. "Complexe canalaires KCa/Ca sensibles aux éther-lipides : régulation de la signalisation calcique dans la migration de cellules cancéreuses". Thesis, Tours, 2015. http://www.theses.fr/2015TOUR4032.
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La formation de métastases est la cause majeure des décès par cancer. Le développement de métastases est consécutif à une série d‟événements complexes tels que la migration, l‟invasion et la prolifération cellulaire. Le canal potassique SK3 (membre de la famille des SKCa) régule la migration des cellules cancéreuses du sein et favorise le développement de métastases osseuses. Le but du projet était d‟identifier et de caractériser les voies d‟entrées calciques associées à la migration cellulaire dépendante du canal SK3 dans différents cancers (sein, colon et prostate). Nous avons pu mettre en évidence que les canaux Ca2+qui étaient associés au canal SK3 variaient en fonction du cancer et régulaient la migration cellulaire dépendante du canal SK3. De plus, nous avons montré que la localisation de ces complexes KCa/Ca2+ dans les radeaux lipidiques était importante pour leur régulation et leur fonction. Ainsi, la délocalisation de ces complexes hors des radeaux lipidiques par des alkyl-phospholipides est un moyen permettant de moduler la migration des cellules exprimant le canal SK3 et le développement de métastasesIn most cases of cancer, metastasis and not the primary tumor per se is the main cause of mortality. To establish secondary growth in distant organs cancer cells must develop an enhanced propensity to migrate. The key objective of this thesis proposes that some actors of Ca2+ signaling (Orai, and TRPC, STIM) coupled to SK3 channel would form complexes that play a critical role in cell migration of various cancers (breast, colon and prostate). Furthermore we showed that the localization of these channels complexes in lipid-rafts is essential to their regulation and function. Thus, the delocalization of these complexes of lipid-raft outside by alkyl-phospholipids could be a new way to modulate the SK3/Ca2+ dependent cell migration and metastasis development