Demonstration of a tumor suppressor function for the protein tyrosine-kinase FES in melanoma

Le mélanome est un cancer de la peau agressif et au mauvais pronostic. Si de nouvelles solutions thérapeutiques efficaces ont été développées, les taux de réponses sont variables et transitoires. Découvrir de nouveaux mécanismes oncogéniques dans cette pathologie reste donc nécessaire. Durant mes travaux, j’ai pu démontrer que la protéine tyrosine-kinase FES est exprimée dans les mélanocytes normaux. Cette expression est largement perdue dans un panel de lignées cellulaires de mélanome, au niveau protéique et transcriptionnel ainsi que dans des cultures primaires d’échantillons de patients. La perte de FES est due à une hyper-méthylation de son promoteur et est réversible. En ré-exprimant FES de manière stable dans deux lignées cellulaires de mélanomes, j’ai montré que cette réexpression entraînait une diminution des capacités oncogéniques des cellules. De plus, en analysant les données d’une cohorte de mélanomes (TCGA), j’ai pu établir qu’une diminution importante ou une perte d’expression de FES se retrouve dans près de 40% des patients, et qu’elle est corrélée à une hyper-méthylation du gène FES. Les patients ayant une faible expression de FES présentent un moins bon pronostic soulignant l’importance de ce phénomène. Enfin, en croisant un modèle murin déficient pour le gène Fes avec un modèle de mélanome, nous observons que les tumeurs sous fond Fes KO sont plus prolifératives et plus volumineuses.Ainsi, par des analyses in vitro, sur des données de patients ou en croisant des modèles murins, j’ai pu démontrer que FES est exprimée au niveau des mélanocytes normaux et y exerce un rôle de suppresseur de tumeur.Among skin cancers, melanoma is the most aggressive and has the worst prognosis. In the last years, new therapeutic tools have been developed but responses differ between patients and are often transient due to resistance mechanisms. This highlights the need to improve understanding of molecular mechanisms of the disease. During my thesis, I have shown for the first time that FES tyrosine kinase is expressed in normal melanocytes, and that its expression is lost at the protein and RNA levels in most melanoma cell lines. The same result is observed in a panel of 12 patients’ short-term cultures. The lack of expression is due to FES promoter hyper-methylation and can be reverted using a hypomethylating agent. By restoring FES expression in two melanoma cell lines, I observe a decrease of oncogenic properties of the cells. Moreover, the analysis of the TCGA data on melanoma indicate that FES expression is strongly decreased or lost in about 40% of patients, and that this loss of expression is correlated with FES promoter methylation. Importantly, patients with low level of FES mRNA have poor prognosis compared to FES expressing patients. Finally, Fes knock-out mice crossed with an inducible melanoma mouse model indicate that tumors proliferation and size are more important under a Fes KO background.In conclusion, by using melanoma cells in vitro, data from melanoma patients and mouse models, I have demonstrated that FES is expressed in normal melanocytes and clearly plays a tumor suppressor role.in melanoma

An essential pathway links FLT3-ITD, HCK and CDK6 in acute myeloid leukemia

CDK4/CDK6 and RB proteins drive the progression through the G1 phase of the cell cycle. In acute myeloid leukemia (AML), the activity of the CDK/Cyclin D complex is increased. The mechanism involved is unknown, as are the respective roles played by CDK4 or CDK6 in this process. Here, we report that AML cells carrying FLT3-ITD mutations are dependent on CDK6 for cell proliferation while CDK4 is not essential. We showed that FLT3-ITD signaling is responsible for CDK6 overexpression, through a pathway involving the SRC-family kinase HCK. Accordingly, FLT3-ITD failed to transform primary hematopoietic progenitor cells from Cdk6-/- mice. Our results demonstrate that CDK6 is the primary target of CDK4/CDK6 inhibitors in FLT3-ITD positive AML. Furthermore, we delineate an essential protein kinase pathway -FLT3/HCK/CDK6- in the context of AML with FLT3-ITD mutations.This project was supported by La Ligue Contre le Cancer (Equipe labelisee) and a grant from the Fondation ARC pour la Recherche sur le Cancer

Gender Differences in Legal Disputes: The Case of French Labor Courts

Cet article porte sur les différences de genre dans les litiges prud’homaux en France. Nous réalisons une analyse empirique de données concernant la phase de conciliation préalable au procès et les décisions des juges lors de la phase de jugement. Pour cela, nous avons créé une nouvelle base de données à partir de documents juridiques. Les résultats sont doubles. Premièrement, les femmes sont moins susceptibles que les hommes de parvenir à une entente avant le procès lorsqu’elles poursuivent leur employeur, sauf dans les cas d’un licenciement. Deuxièmement, nous constatons que, toutes choses égales par ailleurs, les femmes ont plus de chances d’obtenir gain de cause lors de la phase de jugement. Ces résultats suggèrent que les femmes portent, en moyenne, des affaires de meilleure qualité devant le conseil des prud’hommes. Cet effet pourrait s’expliquer par les revendications initiales qui sont portées contre les employeurs, ainsi que par les différences de comportement de négociation pendant la phase de conciliation préalable au procès.This paper focuses on gender differences in French Labor Courts. We empirically investigate data from the pretrial conciliation phase and the judges’ decisions in the trial phase. For that purpose, we compiled a novel database from legal documents. The results are twofold. First, women are less likely to reach pretrial agreement compared to men when they sue their employer, except for dismissal cases. Second, we find that all things being equal, women are more likely to succeed in the trial phase. Taken together, these results suggest that women bring, on average, higher quality cases to the French Labor Court. This effect might be explained by the intitial demands that are brought against the employers, as well as gender differences in bargaining behavior during the pretrial conciliation phase

L’agglomération secondaire de Famars/<i>Fanum Martis</i> (Nord) durant l’Antiquité tardive : d’un pôle commercial au centre militaire

International audienceFanum Martis, present day Famars, a small Roman town unmentioned on the Peutinger map, nor in the Antonine itinerary, seems to have been an important economic actor within the Nervian territory and for its neighboring regions. The first major evidence of a Roman settlement goes back to the Tiberian or Claudian period, although some older vestiges exist. The presence of considerable amounts of raw material (clay deposits, sandstone and iron ore) has enabled its development from the end of the 1st c. AD onwards, and this to the detriment of Bavay, the territory’s Capital town. The unrest at the end of the 3rd c. has brought about an extensive campagne of reinforcement of the town walls all over the North of Gaul, amplified during the 4th c. and is concerning Famars. Its strategic position, controlling the river Scheldt and the Roman roads Bavay-Cambrai and Bavay-Tournai, may explain why Famars received during the 5th c. a praefectus laetorum Nerviorum Fanomantis Belgicae Secundae, as indicated in the Notitia Dignitatum, pars Occidentalis XLII. The Late Roman castrum, whose building is simultaneous to the city’s rapid demolition, occurred around 320 AD. However, several artefacts indicate a military presence well before. The fortification will be occupied until Carolingian times, when finally the urban centre is transferred to Valenciennes.Fanum Martis, actuelle Famars, est une agglomération secondaire inconnue de l’Itinéraire d’Antonin ou de la Table de Peutinger, mais importante dans l’économie du territoire nervien et des régions voisines. Les premiers indices d’occupation antique importants datent de l’époque tibéro-claudienne, bien qu’existent des traces plus anciennes. Les matières premières de son sous-sol (argile, grès, minerai de fer) ont permis son développement au détriment de la capitale Bavay dès la fin du Ier s. apr. J.-C. Les troubles de la fin du IIIe s. apr. J.-C. ont entraîné dans le nord de la Gaule une campagne de fortification des agglomérations, qui s’amplifie au cours du IVe s. et concerne Famars. Sa position stratégique, permettant un contrôle de l’Escaut et des voies Bavay-Cambrai et Bavay-Tournai, peut expliquer pourquoi elle accueille, au Ve s., un praefectus laetorum Nerviorum Fanomantis Belgicae Secundae comme indiqué dans la Notitia Dignitatum, pars Occidentalis Occ. XLII. Le castrum, dont la construction est simultanée au démantèlement très rapide de la ville, est édifié vers 320 apr. J.-C. Toutefois, divers artefacts attestent une fréquentation militaire antérieure à cette période. Le secteur de la fortification sera occupé jusqu’à l’époque carolingienne, au cours de laquelle le centre urbain est transféré à Valenciennes

Social preferences across different populations: Meta-analyses on the ultimatum game and dictator game

International audienceWe perform meta-regressions on a single database containing 96 observations of simple ultimatum games and 144 observations of simple dictator games to disentangle the fairness hypothesis based on the degree of economic development of a country. According to the fairness hypothesis, o ers in the two games should not di er if they were motivated by a subject's fairness concerns. Using the di erence across countries between o ers in ultimatum and dictator games, we address the e ect of being exposed to the market mechanism on pure fairness concerns and other-regarding, expectations-driven fairness. Our results show in particular that the lower the level of economic development in a country, the less likely the rejection of the fairness hypothesis

A Graph-Based Approach for Simultaneous Semantic and Instance Segmentation of Plant 3D Point Clouds

Accurate simultaneous semantic and instance segmentation of a plant 3D point cloud is critical for automatic plant phenotyping. Classically, each organ of the plant is detected based on the local geometry of the point cloud, but the consistency of the global structure of the plant is rarely assessed. We propose a two-level, graph-based approach for the automatic, fast and accurate segmentation of a plant into each of its organs with structural guarantees. We compute local geometric and spectral features on a neighbourhood graph of the points to distinguish between linear organs (main stem, branches, petioles) and two-dimensional ones (leaf blades) and even 3-dimensional ones (apices). Then a quotient graph connecting each detected macroscopic organ to its neighbours is used both to refine the labelling of the organs and to check the overall consistency of the segmentation. A refinement loop allows to correct segmentation defects. The method is assessed on both virtual and real 3D point-cloud data sets of Chenopodium album (wild spinach) and Solanum lycopersicum (tomato plant)

A Graph-Based Approach for Simultaneous Semantic and Instance Segmentation of Plant 3D Point Clouds

International audienceAccurate simultaneous semantic and instance segmentation of a plant 3D point cloud is critical for automatic plant phenotyping. Classically, each organ of the plant is detected based on the local geometry of the point cloud, but the consistency of the global structure of the plant is rarely assessed. We propose a two-level, graph-based approach for the automatic, fast and accurate segmentation of a plant into each of its organs with structural guarantees. We compute local geometric and spectral features on a neighbourhood graph of the points to distinguish between linear organs (main stem, branches, petioles) and two-dimensional ones (leaf blades) and even 3-dimensional ones (apices). Then a quotient graph connecting each detected macroscopic organ to its neighbors is used both to refine the labelling of the organs and to check the overall consistency of the segmentation. A refinement loop allows to correct segmentation defects. The method is assessed on both synthetic and real 3D point-cloud data sets of Chenopodium album (wild spinach) and Solanum lycopersicum (tomato plant)

Characterization of S628N: a novel KIT mutation found in a metastatic melanoma

International audienceIMPORTANCE: The KIT receptor is mutated in approximately 15% of acral, mucosal, and chronic, sun-damaged melanomas. The status of KIT mutations is of interest because they usually are mutually exclusive with N-RAS and B-RAF mutations and because of the availability of KIT kinase inhibitors in the clinic. Some recurrent KIT mutations are well characterized; others are poorly described.OBSERVATIONS: We describe a novel KIT mutation in a patient with metastatic melanoma. The mutation, located in exon 13, resulted in S628N substitution in the KIT receptor. Using all-atom molecular dynamics simulations, biochemical assays, and cell-based assays, we showed that the mutation is a bona fide gain-of-function oncogenic mutation. Furthermore,we evaluated the sensitivity of the mutant to imatinib and dasatinib.CONCLUSIONS AND RELEVANCE: We report a novel KIT gain-of-function mutation with S628N substitution (exon 13) and show that it is sensitive to imatinib in vitro. Therefore, patients with this mutation may be eligible for KIT kinase inhibitor–based therapy. Further studies are needed to evaluate the clinical benefit of such therapy

Management of common pool resources in a nation-wide experiment

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Improvement of the quality of BRAF testing in melanomas with nationwide external quality assessment, for the BRAF EQA group.

International audienceBACKGROUND: Knowledge about tumour gene mutation status is essential for the treatment of increasing numbers of cancer patients, and testing quality has a major impact on treatment response and cost. In 2012, 4,629 tests for BRAF p.V600 were performed in France, in patients with melanomas. METHODS: Two batches of unstained melanoma sections were sent, in May and November 2012, to the 46 laboratories supported by the French National Institute of Cancer (INCa). An external quality assessment (EQA) evaluated mutation status, response times and compliance with INCa recommendations. RESULTS: All the French laboratories involved in testing participated in the EQA. Fourteen different methods were used to detect BRAF mutations, most consisting of combinations of in-house techniques. False responses were noted in 25/520 cases (4.8%), 11 of which concerned confusion between p.V600E and p.V600K. Thus, 2.7% of responses would have led to inappropriate treatment. Within six months, mean response times decreased from 22 to 12 days (P<0.001), and the percentage of samples evaluated by a pathologist for tumour cell content increased, from 75.2% to 96.9% (P<0.001). CONCLUSION: Despite the use of non-certified methods, the false response rate was low. Nationwide EQA can improve the quality of molecular pathology tests on tumours