Contrôle de l'anoïkis par les petites GTPases de la famille Rho

MONTPELLIER-BU Sciences (341722106) / SudocSudocFranceF

Etude de la modulation de l'apoptose liée au virus de l'hépatite C (VHC)

MONTPELLIER-BU Sciences (341722106) / SudocSudocFranceF

Contrôle de l'adhésion et de la migration en cohortes des hépatocytes par le TGF-beta (où il est question d'adhésion à la fibronectine)

La cytokine TGF-beta possède des rôles essentiels dans le développement embryonnaire, l'homéostasie et des pathologies comme les maladies fibrotiques et cancéreuses. Son action est généralement cytostatique et cytotoxique pour les épithéliums et stimulatrice pour le mésenchyme. Dans les carcinomes hépatocellulaires, le TGF-beta semble se comporter initialement comme un suppresseur de tumeur. Cependant l'augmentation quasi-systématique de son niveau indique que plus tardivement il joue un rôle dans la promotion de la progression tumorale. En particulier, le TGF-beta pourrait promouvoir les métastases en stimulant la migration cellulaire. Le travail de cette thèse a consisté à mettre en évidence le rôle de cette cytokine dans l'adhésion à la matrice et la migration des hépatocytes. Nous avons montré que le TGF-beta stimule l'expression de l'intégrine alpha5 et de son ligand matriciel spécifique, la fibronectine. La mise en place d'un modèle de migration en cohorte à permis de montré que la cytokine dirige la migration des hépatocytes vers la migration continue sur des fibres de fibronectine. Dans des conditions empêchant l'adhésion à ce support matriciel, le mode de migration devient aléatoire, évoquant un comportement exploratoire de cellules tumorales. De plus, nous avons caractérisé le mode de migration des cohortes hépatocytaires qui semble être dirigé par une à trois cellules directrices qui traînent le reste de la cohorte. Ce travail permet donc de mieux comprendre le rôle que le TGF-beta pourrait avoir dans la progression tumorale au niveau de son contrôle de la migration cellulaire, qui permet d'abord aux tumeurs de s'étendre puis d'envahir d'autres organesTGF-beta is a cytokine with a strong impact on liver physiology and pathology. It has a growth inhibitory action on healthy cells but, secreted in tumors, it has a growth-provoking function on transformed hepatocytes. We observed that TGF-beta induces dramatic alterations of hepatocytes adhesion due to a change of the pattern of expression of integrin receptors, in particular the over-expression of the alpha5beta1 complex, and its specific ligand, the fibronectin. This altered specificity of anchorage to the extracellular matrix gave rise to changes in cells' collective motility: a persistent, directional movement of cohorts became dependent on adhesion to fibronectin, its absence leading to random, oscillatory motility. These results suggest a novel role for TGF-beta in the control of collective migration of epithelial cellsMONTPELLIER-BU Sciences (341722106) / SudocSudocFranceF

What makes cells move: requirements and obstacles for spontaneous cell motility.

International audienceMovement of individual cells and of cellular cohorts, chains or sheets requires physical forces that are established through interactions of cells with their environment. In vivo, migration occurs extensively during embryonic development and in adults during wound healing and tumorigenesis. In order to identify the molecular events involved in cell movement, in vitro systems have been developed. These have contributed to the definition of a number of molecular pathways put into play in the course of migratory behaviours, such as mesenchymal and amoeboid movement. More recently, our knowledge of migratory modes has been enriched by analyses of cells exploring and moving through three-dimensional (3D) matrices. While the cells' morphologies differ in 2D and 3D environments, the basic mechanisms that put a cellular body into motion are remarkably similar. Thus, in both 2D and 3D, the polarity of the migrating cell is initially defined by a specific subcellular localization of signalling molecules and components of molecular machines required for motion. While the polarization can be initiated either in response to extracellular signalling or be a chance occurrence, it is reinforced and sustained by positive feedback loops of signalling molecules. Second, adhesion to a substratum is necessary to generate forces that will propel the cell engaged in either mesenchymal or ameboid migration. For collective cell movement, intercellular coordination constitutes an additional requirement: a cell cohort remains stationary if individual cells pull in opposite directions. Finally, the availability of space to move into is a general requirement to set cells into motion. Lack of free space is probably the main obstacle for migration of most healthy cells in an adult multicellular organism. Thus, the requirements for cell movement are both intrinsic to the cell, involving coordinated signalling and interactions with molecular machines, and extrinsic, imposed by the physicochemical nature of the environment. In particular, the geometry and stiffness of the support act on a range of signalling pathways that induce specific cell migratory responses. These issues are discussed in the present review in the context of published work and our own data on collective migration of hepatocyte cohorts

Activation of ERK, Controlled by Rac1 and Cdc42 via Akt, Is Required for Anoikis

International audienceWe have recently reported that two Rho family GTPases, Rac1 and Cdc42, are intimately involved in the control of cell survival of murine fibroblasts linked to adherence to the extracellular matrix. Inhibition of either Rac1 or Cdc42 signaling in adherent cells mimics the loss of anchorage and efficiently induces apoptosis in both immortalized and primary cells. In both cases cell death is dependent on the wild-type p53 tumor suppressor and is accompanied by activation of endogenous p53. Here, we describe that the inhibition of Rac1 or Cdc42 signaling leads to MAPK ERK activation via a pathway involving PI(3)K, Akt, Raf, and MEK, but not Ras. The moderate level of ERK activation that accompanies anoikis is an essential component of proapoptotic signaling; whereas sustained, high-intensity ERK signaling promotes survival in the same experimental system

Extinction of Rac1 and Cdc42Hs signalling defines a novel p53-dependent apoptotic pathway

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Paracrine Behaviors Arbitrate Parasite-Like Interactions Between Tumor Subclones

International audienceExplaining the emergence and maintenance of intratumor heterogeneity is an important question in cancer biology. Tumor cells can generate considerable subclonal diversity, which influences tumor growth rate, treatment resistance, and metastasis, yet we know remarkably little about how cells from different subclones interact. Here, we confronted two murine mammary cancer cell lines to determine both the nature and mechanisms of subclonal cellular interactions in vitro. Surprisingly, we found that, compared to monoculture, growth of the "winner" was enhanced by the presence of the "loser" cell line, whereas growth of the latter was reduced. Mathematical modeling and laboratory assays indicated that these interactions are mediated by the production of paracrine metabolites resulting in the winner subclone effectively "farming" the loser. Our findings add a new level of complexity to the mechanisms underlying subclonal growth dynamics

Anti-apoptotic activity of p53 maps to the COOH-terminal domain and is retained in a highly oncogenic natural mutant

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