Publications (312) View all
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Article: α-catenin and vinculin cooperate to promote high E-cadherin-based adhesion strength.
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ABSTRACT: Maintaining cell cohesivity within tissues requires that intercellular adhesions develop sufficient strength to support traction forces applied by myosin motors and by neighbouring cells. Cadherins are transmembrane receptors that mediate intercellular adhesion. Cadherin cytoplasmic domain recruits several partners, including catenins and vinculin, at sites of cell-cell adhesion. Our study used force measurements to address the role of αE-catenin and vinculin in the regulation of the strength of E-cadherin-based adhesion. αE-catenin-deficient cells display only weak aggregation and fail to strengthen intercellular adhesion over time, a process rescued by the expression of αE-catenin or chimeric E-cadherin-αE-catenins, including a chimera lacking the αE-catenin dimerization domain. Interestingly, an αE-catenin mutant lacking the modulation and actin-binding domains restores cadherin-dependent cell-cell contacts but cannot strengthen intercellular adhesion. The expression of αE-catenin mutated in its vinculin-binding site is defective in its ability to rescue cadherin-based adhesion strength in cells lacking αE-catenin. Vinculin depletion or the overexpression of the αE-catenin modulation domain strongly decreases E-cadherin-mediated adhesion strength. This supports the notion that both molecules are required for intercellular contact maturation. Furthermore, stretching of cell doublets increases vinculin recruitment and α18 anti-αE-catenin conformational epitope immunostaining at cell-cell contacts. Taken together, our results indicate that αE-catenin and vinculin cooperatively support intercellular adhesion strengthening, likely via a mechanoresponsive link between the E-cadherin-β-catenin complexes and the underlying actin cytoskeleton.Journal of Biological Chemistry 02/2013; 288(7):4957-4969. · 4.77 Impact Factor -
Article: Translating metastasis-related biomarkers to the clinic-progress and pitfalls.
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ABSTRACT: In the context of metastatic disease, preclinical models have been used primarily to decipher different steps of the metastatic cascade. Numerous molecular processes operate in these model systems, but none of these has been successfully translated to the clinic. We discuss some of the successes and failures of preclinical models in metastasis research and suggest some of the clues for more clinically relevant research. These potential avenues of research include: the use of adequate statistical methods and well-annotated cohorts in biomarker discovery; an objective assessment of the level of evidence provided by each biomarker; the development of robust molecular or cellular surrogates of metastasis in patients; and original designs for clinical trials.Nature Reviews Clinical Oncology 02/2013; · 11.96 Impact Factor -
Article: Screening therapeutic EMT blocking agents in a three-dimensional microenvironment.
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ABSTRACT: Epithelial-mesenchymal transition (EMT) plays a critical role in the early stages of dissemination of carcinoma leading to metastatic tumors, which are responsible for over 90% of all cancer-related deaths. Current therapeutic regimens, however, have been ineffective in the cure of metastatic cancer, thus an urgent need exists to revisit existing protocols and to improve the efficacy of newly developed therapeutics. Strategies based on preventing EMT could potentially contribute to improving the outcome of advanced stage cancers. To achieve this goal new assays are needed to identify targeted drugs capable of interfering with EMT or to revert the mesenchymal-like phenotype of carcinoma to an epithelial-like state. Current assays are limited to examining the dispersion of carcinoma cells in isolation in conventional 2-dimensional (2D) microwell systems, an approach that fails to account for the 3-dimensional (3D) environment of the tumor or the essential interactions that occur with other nearby cell types in the tumor microenvironment. Here we present a microfluidic system that integrates tumor cell spheroids in a 3D hydrogel scaffold, in close co-culture with an endothelial monolayer. Drug candidates inhibiting receptor activation or signal transduction pathways implicated in EMT have been tested using dispersion of A549 lung adenocarcinoma cell spheroids as a metric of effectiveness. We demonstrate significant differences in response to drugs between 2D and 3D, and between monoculture and co-culture.Integrative Biology 11/2012; · 4.51 Impact Factor -
Article: Targeting Pathways Contributing to Epithelial-Mesenchymal Transition (EMT) in Epithelial Ovarian Cancer.
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ABSTRACT: Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Discovery of novel therapeutic opportunities for EOC is important for the improvement of clinical outcome of the patients. Emerging evidence is suggesting that epithelial-mesenchymal transition (EMT) plays a crucial role in the aggressiveness in EOC including increasing migration and invasion ability, contributing to chemoresistance and cancer stem cell populations. Targeting EMT in EOC thus offers an attractive therapeutic option.Current drug targets 10/2012; · 3.93 Impact Factor -
Article: Epithelial-mesenchymal transitions: insights from development.
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ABSTRACT: Epithelial-mesenchymal transition (EMT) is a crucial, evolutionarily conserved process that occurs during development and is essential for shaping embryos. Also implicated in cancer, this morphological transition is executed through multiple mechanisms in different contexts, and studies suggest that the molecular programs governing EMT, albeit still enigmatic, are embedded within developmental programs that regulate specification and differentiation. As we review here, knowledge garnered from studies of EMT during gastrulation, neural crest delamination and heart formation have furthered our understanding of tumor progression and metastasis.Development 10/2012; 139(19):3471-86. · 6.60 Impact Factor
