Implication de deux partenaires de DCC dans le développement et la tumorigenèse

DCC is a tramsmembrane protein, receptor of netrin-1. DCC belongs to the dependence receptor family, which have a dual functionality. Indeed, they are not inactive when not bound by their ligand but instead they actively induce apoptosis thus explaining that they are tumor suppressors. My PhD project contains 2 axes :Axe 1 : Involvement of DCC/netrin-1 during lymphomagenesis. We demonstrated that the gene expression of DCC and netrin-1 is deregulated in mantle cell lymphoma (MCL) and in diffuse large b cell lymphoma (DLBCL) : netrin-1 expression is upregulated in MCL and Activated B-Cell DLBCL. On the opposit, DCC expression is downregulated in Germinal Centre DLBCL. From a therapeutical point of view, reinducing DCC's apoptotis by blocking its interaction with netrin-1 triggers tumor volum in a xenograft model. DCC-netrin-1 might also be involved in extra-nodal lymphoma development. Axe 2 : Functional caracterization of ADAMTSL1.DCC's ortholog in C. elegans, UNC-40, functionnaly interacts with the protein MADD-4 during the setting up of neuromuscular junctions. We did not find any such connexion between DCC and MADD-4's ortholog in mammals, ADAMTSL1. The function of ADAMTSL1 is unknown and we used different in vitro and in vivo models including a mouse model invalidated for this gene to unravel the function of this matricial protein, notably in muscular and cartilaginous tissusDCC est un récepteur transmembranaire ayant pour ligand la nétrine-1. DCC appartient à la famille des récepteurs à dépendance, qui ont la particularité de ne pas rester inactifs en absence de ligand mais, au contraire, d'induire activement l'apoptose lorsqu'ils sont dans un état non lié, ce qui explique leur fonction suppresseur de tumeur. Mon travail de thèse s'est articulé autour de deux axes de recherche: Axe 1 : Implication du couple DCC/nétrine-1 dans la lymphomagenèse. Nous avons montrer que l'expression du couple DCC/nétrine-1 est dérégulée dans les lymphomes du manteau (LM) ainsi que dans les lymphomes diffus à grandes cellules B (LDGC-B) : l'expression de la nétrine-1 est augmentée dans les LM et les LDGC-B de type ABC, alors que l'expression de DCC est diminuée dans les LDGC-B de type GC. Sur le plan thérapeutique, rétablir l'apoptose induite par DCC en bloquant l'interaction avec son ligand nétrine-1 induit une diminution du volume tumoral dans un modèle de xénogreffe. Le couple DCC/nétrine-1 pourrait également jouer un rôle dans le développement des lymphomes extranodaux. Axe 2 : Caractérisation fonctionnelle de la protéine ADAMTSL-1.L'orthologue de DCC chez C. elegans, UNC-40 interagit fonctionnellement avec la protéine MADD-4 lors de la mise en place des jonctions neuromusculaires. Nous n'avons pas établi l'existence d'une telle connexion entre DCC et l'orthologue de MADD-4 chez les Mammifères, ADAMTSL1. La fonction d'ADAMTSL1 étant inconnue, nous avons utilisé différents systèmes in vitro et in vivo, dont un modèle murin invalidé constitutivement pour ce gène, pour déterminer la fonction de cette protéine matricielle, notamment dans les tissus musculaires et cartilagineu

Implication de deux partenaires de DCC dans le développement et la tumorigenèse

DCC is a tramsmembrane protein, receptor of netrin-1. DCC belongs to the dependence receptor family, which have a dual functionality. Indeed, they are not inactive when not bound by their ligand but instead they actively induce apoptosis thus explaining that they are tumor suppressors. My PhD project contains 2 axes :Axe 1 : Involvement of DCC/netrin-1 during lymphomagenesis. We demonstrated that the gene expression of DCC and netrin-1 is deregulated in mantle cell lymphoma (MCL) and in diffuse large b cell lymphoma (DLBCL) : netrin-1 expression is upregulated in MCL and Activated B-Cell DLBCL. On the opposit, DCC expression is downregulated in Germinal Centre DLBCL. From a therapeutical point of view, reinducing DCC's apoptotis by blocking its interaction with netrin-1 triggers tumor volum in a xenograft model. DCC-netrin-1 might also be involved in extra-nodal lymphoma development. Axe 2 : Functional caracterization of ADAMTSL1.DCC's ortholog in C. elegans, UNC-40, functionnaly interacts with the protein MADD-4 during the setting up of neuromuscular junctions. We did not find any such connexion between DCC and MADD-4's ortholog in mammals, ADAMTSL1. The function of ADAMTSL1 is unknown and we used different in vitro and in vivo models including a mouse model invalidated for this gene to unravel the function of this matricial protein, notably in muscular and cartilaginous tissusDCC est un récepteur transmembranaire ayant pour ligand la nétrine-1. DCC appartient à la famille des récepteurs à dépendance, qui ont la particularité de ne pas rester inactifs en absence de ligand mais, au contraire, d'induire activement l'apoptose lorsqu'ils sont dans un état non lié, ce qui explique leur fonction suppresseur de tumeur. Mon travail de thèse s'est articulé autour de deux axes de recherche: Axe 1 : Implication du couple DCC/nétrine-1 dans la lymphomagenèse. Nous avons montrer que l'expression du couple DCC/nétrine-1 est dérégulée dans les lymphomes du manteau (LM) ainsi que dans les lymphomes diffus à grandes cellules B (LDGC-B) : l'expression de la nétrine-1 est augmentée dans les LM et les LDGC-B de type ABC, alors que l'expression de DCC est diminuée dans les LDGC-B de type GC. Sur le plan thérapeutique, rétablir l'apoptose induite par DCC en bloquant l'interaction avec son ligand nétrine-1 induit une diminution du volume tumoral dans un modèle de xénogreffe. Le couple DCC/nétrine-1 pourrait également jouer un rôle dans le développement des lymphomes extranodaux. Axe 2 : Caractérisation fonctionnelle de la protéine ADAMTSL-1.L'orthologue de DCC chez C. elegans, UNC-40 interagit fonctionnellement avec la protéine MADD-4 lors de la mise en place des jonctions neuromusculaires. Nous n'avons pas établi l'existence d'une telle connexion entre DCC et l'orthologue de MADD-4 chez les Mammifères, ADAMTSL1. La fonction d'ADAMTSL1 étant inconnue, nous avons utilisé différents systèmes in vitro et in vivo, dont un modèle murin invalidé constitutivement pour ce gène, pour déterminer la fonction de cette protéine matricielle, notamment dans les tissus musculaires et cartilagineu

Involvement of two DCC's interactors during development and tumorigenesis

DCC est un récepteur transmembranaire ayant pour ligand la nétrine-1. DCC appartient à la famille des récepteurs à dépendance, qui ont la particularité de ne pas rester inactifs en absence de ligand mais, au contraire, d'induire activement l'apoptose lorsqu'ils sont dans un état non lié, ce qui explique leur fonction suppresseur de tumeur. Mon travail de thèse s'est articulé autour de deux axes de recherche: Axe 1 : Implication du couple DCC/nétrine-1 dans la lymphomagenèse. Nous avons montrer que l'expression du couple DCC/nétrine-1 est dérégulée dans les lymphomes du manteau (LM) ainsi que dans les lymphomes diffus à grandes cellules B (LDGC-B) : l'expression de la nétrine-1 est augmentée dans les LM et les LDGC-B de type ABC, alors que l'expression de DCC est diminuée dans les LDGC-B de type GC. Sur le plan thérapeutique, rétablir l'apoptose induite par DCC en bloquant l'interaction avec son ligand nétrine-1 induit une diminution du volume tumoral dans un modèle de xénogreffe. Le couple DCC/nétrine-1 pourrait également jouer un rôle dans le développement des lymphomes extranodaux. Axe 2 : Caractérisation fonctionnelle de la protéine ADAMTSL-1.L'orthologue de DCC chez C. elegans, UNC-40 interagit fonctionnellement avec la protéine MADD-4 lors de la mise en place des jonctions neuromusculaires. Nous n'avons pas établi l'existence d'une telle connexion entre DCC et l'orthologue de MADD-4 chez les Mammifères, ADAMTSL1. La fonction d'ADAMTSL1 étant inconnue, nous avons utilisé différents systèmes in vitro et in vivo, dont un modèle murin invalidé constitutivement pour ce gène, pour déterminer la fonction de cette protéine matricielle, notamment dans les tissus musculaires et cartilagineuxDCC is a tramsmembrane protein, receptor of netrin-1. DCC belongs to the dependence receptor family, which have a dual functionality. Indeed, they are not inactive when not bound by their ligand but instead they actively induce apoptosis thus explaining that they are tumor suppressors. My PhD project contains 2 axes :Axe 1 : Involvement of DCC/netrin-1 during lymphomagenesis. We demonstrated that the gene expression of DCC and netrin-1 is deregulated in mantle cell lymphoma (MCL) and in diffuse large b cell lymphoma (DLBCL) : netrin-1 expression is upregulated in MCL and Activated B-Cell DLBCL. On the opposit, DCC expression is downregulated in Germinal Centre DLBCL. From a therapeutical point of view, reinducing DCC's apoptotis by blocking its interaction with netrin-1 triggers tumor volum in a xenograft model. DCC-netrin-1 might also be involved in extra-nodal lymphoma development. Axe 2 : Functional caracterization of ADAMTSL1.DCC's ortholog in C. elegans, UNC-40, functionnaly interacts with the protein MADD-4 during the setting up of neuromuscular junctions. We did not find any such connexion between DCC and MADD-4's ortholog in mammals, ADAMTSL1. The function of ADAMTSL1 is unknown and we used different in vitro and in vivo models including a mouse model invalidated for this gene to unravel the function of this matricial protein, notably in muscular and cartilaginous tissu

Insulin-feedback via PI3K-C2 alpha activated PKB alpha/Akt1 is required for glucose-stimulated insulin secretion

Phosphatidylinositide 3-kinases (PI3Ks) play central roles in insulin signal transduction. While the contribution of class Ia PI3K members has been extensively studied, the role of class II members remains poorly understood. The diverse actions of class II PI3K-C2 alpha have been attributed to its lipid product PI(3) P. By applying pharmacological inhibitors, transient overexpression and small-interfering RNA-based knockdown of PI3K and PKB/Akt isoforms, together with PI-lipid profiling and live-cell confocal and total internal reflection fluorescence microscopy, we now demonstrate that in response to insulin, PI3K-C2 alpha generates PI(3,4) P-2, which allows the selective activation of PKB alpha/Akt1. Knockdown of PI3K-C2 alpha expression and subsequent reduction of PKB alpha/Akt1 activity in the pancreatic beta-cell impaired glucose-stimulated insulin release, at least in part, due to reduced glucokinase expression and increased AS160 activity. Hence, our results identify signal transduction via PI3K-C2 alpha as a novel pathway whereby insulin activates PKB/Akt and thus discloses PI3K-C2 alpha as a potential drugable target in type 2 diabetes. The high degree of codistribution of PI3K-C2 alpha and PKB alpha/Akt1 with insulin receptor B type, but not A type, in the same plasma membrane microdomains lends further support to the concept that selectivity in insulin signaling is achieved by the spatial segregation of signaling events.-Leibiger, B., Moede, T., Uhles, S., Barker, C. J., Creveaux, M., Domin, J., Berggren, P.-O., Leibiger, I. B. Insulin-feedback via PI3K-C2 alpha activated PKB alpha/Akt1 is required for glucose-stimulated insulin secretion. FASEB J. 24, 1824-1837 (2010). www.fasebj.or

Combining chemotherapeutic agents and netrin-1 interference potentiates cancer cell death

The secreted factor netrin-1 is upregulated in a fraction of human cancers as a mechanism to block apoptosis induced by netrin-1 dependence receptors DCC and UNC5H. Targeted therapies aiming to trigger tumour cell death via netrin-1/receptors interaction interference are under preclinical evaluation. We show here that Doxorubicin, 5-Fluorouracil, Paclitaxel and Cisplatin treatments trigger, in various human cancer cell lines, an increase of netrin-1 expression which is accompanied by netrin-1 receptors increase. This netrin-1 upregulation which appears to be p53-dependent is a survival mechanism as netrin-1 silencing by siRNA is associated with a potentiation of cancer cell death upon Doxorubicin treatment. We show that candidate drugs interfering with netrin-1/netrin-1 receptors interactions potentiate Doxorubicin, Cisplatin or 5-Fluorouracil-induced cancer cell death in vitro. Moreover, in a model of xenografted nude mice, we show that systemic Doxorubicin treatment triggers netrin-1 upregulation in the tumour but not in normal organs, enhancing and prolonging tumour growth inhibiting effect of a netrin-1 interfering drug. Together these data suggest that combining conventional chemotherapies with netrin-1 interference could be a promising therapeutic approach

Inactivation of the putative suppressor gene DOK1 by promoter hypermethylation in primary human cancers

The DOK1 gene is a putative tumour suppressor gene located on the human chromosome 2p13 which is frequently rearranged in leukaemia and other human tumours. We previously reported that the DOK1 gene can be mutated and its expression down-regulated in human malignancies. However, the mechanism underlying DOK1 silencing remains largely unknown. We show here that unscheduled silencing of DOK1 expression through aberrant hypermethylation is a frequent event in a variety of human malignancies. DOK1 was found to be silenced in nine head and neck cancer (HNC) cell lines studied and DOK1 CpG hypermethylation correlated with loss of gene expression in these cells. DOK1 expression could be restored via demethylating treatment using 5-aza-2′deoxycytidine. In addition, transduction of cancer cell lines with DOK1 impaired their proliferation, consistent with the critical role of epigenetic silencing of DOK1 in the development and maintenance of malignant cells. We further observed that DOK1 hyperm

Regulation by miR181 Family of the Dependence Receptor CDON Tumor Suppressive Activity in Neuroblastoma

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Targeting netrin-1/DCC interaction in diffuse large B-cell and mantle cell lymphomas

International audienceDCC (Deleted in Colorectal Carcinoma) has been demonstrated to constrain tumor progression by inducing apoptosis unless engaged by its ligand netrin-1. This has been shown in breast and colorectal cancers; however, this tumor suppressive function in other cancers is not established. Using a transgenic mouse model, we report here that inhibition of DCC-induced apoptosis is associated with lymphomagenesis. In human diffuse large B-cell lymphoma (DLBCL), an imbalance of the netrin-1/DCC ratio suggests a loss of DCC-induced apoptosis, either via a decrease in DCC expression in germinal center subtype or by up-regulation of netrin-1 in activated B-cell (ABC) one. Such imbalance is also observed in mantle cell lymphoma (MCL). Using a netrin-1 interfering antibody, we demonstrate both in vitro and in vivo that netrin-1 acts as a survival factor for ABC-DLBCL and MCL tumor cells. Together, these data suggest that interference with the netrin-1/DCC interaction could represent a promising therapeutic strategy in netrin-1-positive DLBCL and MC

Economics and COVID-19: A Bibliometric Analysis of the First Months of Publications

This work discusses a bibliometric analysis of the papers published during 2020 about COVID-19 and three relevant economic keywords: GDP, unemployment, and innovation. Considering different outcomes, a significant diversity of journals without the focus on economic issues publishing articles discussing the economic impacts of the COVID-19 pandemic was observed. The authors have also suggested some correlated dimensions between the number of articles authored by researchers affiliated to different universities of diverse countries and the severity of the pandemic indicators observed for these spaces.info:eu-repo/semantics/publishedVersio