Active YAP promotes pancreatic cancer cell motility, invasion and tumorigenesis in a mitotic phosphorylation-dependent manner through LPAR3.

The transcriptional co-activator Yes-associated protein, YAP, is a main effector in the Hippo tumor suppressor pathway. We recently defined a mechanism for positive regulation of YAP through CDK1-mediated mitotic phosphorylation. Here, we show that active YAP promotes pancreatic cancer cell migration, invasion and anchorage-independent growth in a mitotic phosphorylation-dependent manner. Mitotic phosphorylation is essential for YAP-driven tumorigenesis in animals. YAP reduction significantly impairs cell migration and invasion. Immunohistochemistry shows significant upregulation and nuclear localization of YAP in metastases when compared with primary tumors and normal tissue in human. Mitotic phosphorylation of YAP controls a unique transcriptional program in pancreatic cells. Expression profiles reveal LPAR3 (lysophosphatidic acid receptor 3) as a mediator for mitotic phosphorylation-driven pancreatic cell motility and invasion. Together, this work identifies YAP as a novel regulator of pancreatic cancer cell motility, invasion and metastasis, and as a potential therapeutic target for invasive pancreatic cancer

MUC1 mucin stabilizes and activates hypoxia-inducible factor 1 alpha to regulate metabolism in pancreatic cancer

Aberrant glucose metabolism is one of the hallmarks of cancer that facilitates cancer cell survival and proliferation. Here, we demonstrate that MUC1, a large, type I transmembrane protein that is overexpressed in several carcinomas including pancreatic adenocarcinoma, modulates cancer cell metabolism to facilitate growth properties of cancer cells. MUC1 occupies the promoter elements of multiple genes directly involved in glucose metabolism and regulates their expression. Furthermore, MUC1 expression enhances glycolytic activity in pancreatic cancer cells. We also demonstrate that MUC1 expression enhances in vivo glucose uptake and expression of genes involved in glucose uptake and metabolism in orthotopic implantation models of pancreatic cancer. The MUC1 cytoplasmic tail is known to activate multiple signaling pathways through its interactions with several transcription factors/coregulators at the promoter elements of various genes. Our results indicate that MUC1 acts as a modulator of the hypoxic response in pancreatic cancer cells by regulating the expression/stability and activity of hypoxia-inducible factor-1α (HIF-1α). MUC1 physically interacts with HIF-1α and p300 and stabilizes the former at the protein level. By using a ChIP assay, we demonstrate that MUC1 facilitates recruitment of HIF-1α and p300 on glycolytic gene promoters in a hypoxia-dependent manner. Also, by metabolomic studies, we demonstrate that MUC1 regulates multiple metabolite intermediates in the glucose and amino acid metabolic pathways. Thus, our studies indicate that MUC1 acts as a master regulator of the metabolic program and facilitates metabolic alterations in the hypoxic environments that help tumor cells survive and proliferate under such conditions

Na mira do sucesso : estratégias de combate ao insucesso escolar de alunos estrangeiros

Trabalho de projeto de mestrado, Ciências da Educação (Área de especialização Formação de Adultos), Universidade de Lisboa, Instituto de Educação, 2017Considerando a importância da integração no contexto escolar e consequentemente no sucesso educativo, o presente trabalho projeto, desenvolvido no âmbito do Mestrado em Ciências da Educação, área de especialidade em Formação de Adultos, centra-se na integração de alunos estrangeiros no ensino português, assim como na dinamização de atividades de promoção do seu sucesso escolar. Deste modo, o relatório apresenta como principais temáticas a integração de estrangeiros em Portugal, o insucesso escolar dos alunos estrangeiros e as políticas educativas de combate a este fenómeno, culminando na definição e desenvolvimento de um projeto de combate ao insucesso escolar destinado a este público. O trabalho desenvolvido junto destes jovens nos últimos nove anos e o diagnóstico elaborado no Agrupamento de Escolas João de Barros permitiu compreender a importância de intervir junto da população estrangeira, fomentando o sucesso educativo e a integração no país de acolhimento, uma vez que a taxa de retenção destes jovens está muito acima dos seus colegas autóctones.Considering the importance of integration in the school context, and consequently in educational success, this project, developed in the scope of the master’s degree in Educational Sciences, specialization in Adult Education, focuses on foreign students’ integration at the Portuguese educational system and activities that could be developed to promote their school success. Therefore, the main themes of the report are the integration of foreigners in Portugal, the lack of academic experience from foreign students and educational policies to reduce this barrier, in order to define and develop a project to combat school failure among this cases. The work developed for the last nine years with this students, the diagnostic elaborated in João de Barros Group of Schools, allowed me to understand the importance of an intervention among foreign students, to foment educational success and integration in the host country, bearing in mind that the retention rate in those cases is far above the native students’ average

MUC1 mucin stabilizes and activates hypoxia-inducible factor 1 alpha to regulate metabolism in pancreatic cancer

Aberrant glucose metabolism is one of the hallmarks of cancer that facilitates cancer cell survival and proliferation. Here, we demonstrate that MUC1, a large, type I transmembrane protein that is overexpressed in several carcinomas including pancreatic adenocarcinoma, modulates cancer cell metabolism to facilitate growth properties of cancer cells. MUC1 occupies the promoter elements of multiple genes directly involved in glucose metabolism and regulates their expression. Furthermore, MUC1 expression enhances glycolytic activity in pancreatic cancer cells. We also demonstrate that MUC1 expression enhances in vivo glucose uptake and expression of genes involved in glucose uptake and metabolism in orthotopic implantation models of pancreatic cancer. The MUC1 cytoplasmic tail is known to activate multiple signaling pathways through its interactions with several transcription factors/coregulators at the promoter elements of various genes. Our results indicate that MUC1 acts as a modulator of the hypoxic response in pancreatic cancer cells by regulating the expression/stability and activity of hypoxia-inducible factor-1α (HIF-1α). MUC1 physically interacts with HIF-1α and p300 and stabilizes the former at the protein level. By using a ChIP assay, we demonstrate that MUC1 facilitates recruitment of HIF-1α and p300 on glycolytic gene promoters in a hypoxia-dependent manner. Also, by metabolomic studies, we demonstrate that MUC1 regulates multiple metabolite intermediates in the glucose and amino acid metabolic pathways. Thus, our studies indicate that MUC1 acts as a master regulator of the metabolic program and facilitates metabolic alterations in the hypoxic environments that help tumor cells survive and proliferate under such conditions

Metabolic Regulation of Redox Balance in Cancer

Reactive oxygen species (ROS) are chemically active free radicals produced by partial reduction of oxygen that can activate discrete signaling pathways or disrupt redox homeostasis depending on their concentration. ROS interacts with biomolecules, including DNA, and can cause mutations that can transform normal cells into cancer cells. Furthermore, certain cancer-causing mutations trigger alterations in cellular metabolism that can increase ROS production, resulting in genomic instability, additional DNA mutations, and tumor evolution. To prevent excess ROS-mediated toxicity, cancer-causing mutations concurrently activate pathways that manage this oxidative burden. Hence, an understanding of the metabolic pathways that regulate ROS levels is imperative for devising therapies that target tumor cells. In this review, we summarize the dual role of metabolism as a generator and inhibitor of ROS in cancer and discuss current strategies to target the ROS axis

A Quality Pattern Based Approach for the Analysis and Design of Information Systems

Les modèles conceptuels (MC) jouent un rôle crucial qui est celui de servir de base à l’ensemble du processus de développement d’un système d’information (SI) mais aussi de moyen de communication à la fois au sein de l’équipe de développement et avec les utilisateurs durant les premières étapes de validation. Leur qualité joue par conséquent un rôle déterminant dans le succès du système final. Des études ont montré que la majeure partie des changements que subit un SI concerne des manques ou des défaillances liés aux fonctionnalités attendues. Sachant que la définition de ses fonctionnalités incombe à la phase de l’analyse et conception dont les MC constituent les livrables, il apparaît indispensable pour une méthode de conception de veiller à la qualité des MC qu’elle produit. Notre approche vise les problèmes liés à la qualité de la modélisation conceptuelle en proposant une solution intégrée au processus de développement qui à l’avantage d’être complète puisqu’elle adresse à la fois la mesure de la qualité ainsi que son amélioration. La proposition couvre les aspects suivants: i. Formulation de critères de qualité en fédérant dans un premier temps les travaux existant sur la qualité des MC. En effet, un des manques constaté dans le domaine de la qualité des MC est l’absence de consensus sur les concepts et leurs définitions. Ce travail a été validé par une étude empirique. Ce travail a également permis d’identifier les parties non couverte par la littérature et de les compléter en proposant de nouveaux concepts ou en précisant ceux dont la définition n’était complète. ii. Définition d’un concept (pattern de qualité) permettant de capitaliser les bonnes pratiques dans le domaine de la mesure et de l’amélioration de la qualité des MC. Un pattern de qualité sert à aider un concepteur de SI dans l’identification des critères de qualité applicables à sa spécification, puis de le guider progressivement dans la mesure de la qualité ainsi que dans son amélioration. Sachant que la plupart des approches existantes s’intéresse à la mesure de la qualité et néglige les moyens de la corriger. La définition de ce concept est motivée par la difficulté et le degré d’expertise important qu’exige la gestion de la qualité surtout au niveau conceptuel où le logiciel fini n’est pas encore disponible et face à la diversité des concepts de qualité (critères et métriques) pouvant s’appliquer. iii. Formulation d’une méthode orientée qualité incluant à la fois des concepts, des guides et des techniques permettant de définir les concepts de qualité souhaités, leur mesure et l’amélioration de la qualité des MC. Cette méthode propose comme point d’entrée le besoin de qualité que doit formuler le concepteur. Il est ensuite guidée de manière flexible dans le choix des critères de qualité adaptés jusqu’à la mesure et la proposition de recommandations aidant à l’amélioration de la qualité du MC initial conformément au besoin formulé. iv. Développement d'un prototype "CM-Quality". Notre prototype met en œuvre la méthode proposée et offre ainsi une aide outillé à son application. Nous avons enfin mené deux expérimentations ; la première avait comme objectif de valider les concepts de qualité utilisés et de les retenir. La deuxième visait à valider la méthode de conception guidée par la qualité proposéeConceptual models (CM) serve as the blueprints of information systems and their quality plays decisive role in the success of the end system. It has been witnessed that majority of the IS change-requests result due to deficient functionalities in the information systems. Therefore, a good analysis and design method should ensure that CM are correct and complete, as they are the communicating mediator between the users and the development team. Our approach targets the problems related to conceptual modeling quality by proposing a comprehensive solution. We designed multiple artifacts for different aspects of CM quality. These artifacts include the following: i. Formulation of comprehensive quality criteria (quality attributes, metrics, etc.) by federating the existing quality frameworks and identifying the quality criteria for gray areas. Most of the existing literature on CM quality evaluation represents disparate and autonomous quality frameworks proposing non-converging solutions. Thus, we synthesized (existing concepts proposed by researchers) and added the new concepts to formulate a comprehensive quality approach for conceptual models that also resulted in federating the existing quality frameworks. ii. Formulation of quality patterns to encapsulate past-experiences and good practices as the selection of relevant quality criteria (including quality attributes and metrics) with respect to a particular requirement (or goal) remains trickier for a non-expert user. These quality patterns encapsulate valuable knowledge in the form of established and better solutions to resolve quality problems in CM. iii. Designing of the guided quality driven process encompassing methods and techniques to evaluate and improve the conceptual models with respect to a specific user requirement or goal. Our process guides the user in formulating the desired quality goal, helps him/her in identifying the relevant quality patterns or quality attributes with respect to the quality goal and finally the process helps in evaluating the quality of the model and propose relevant recommendations for improvement. iv. Development of a software prototype “CM-Quality”. Our prototype implements all the above mentioned artifacts and proposes a workflow enabling its users to evaluate and improve CMs efficiently and effectively. We conducted a survey to validate the selection of the quality attributes through the above mentioned federating activity and also conducted three step detailed experiment to evaluate the efficacy and efficiency of our overall approach and proposed artifacts

Correction: MUC1 facilitates metabolomic reprogramming in triple-negative breast cancer.

[This corrects the article DOI: 10.1371/journal.pone.0176820.]

Metabolic reprogramming induced by ketone bodies diminishes pancreatic cancer cachexia

Background: Aberrant energy metabolism is a hallmark of cancer. To fulfill the increased energy requirements, tumor cells secrete cytokines/factors inducing muscle and fat degradation in cancer patients, a condition known as cancer cachexia. It accounts for nearly 20% of all cancer-related deaths. However, the mechanistic basis of cancer cachexia and therapies targeting cancer cachexia thus far remain elusive. A ketogenic diet, a high-fat and low-carbohydrate diet that elevates circulating levels of ketone bodies (i.e., acetoacetate, β-hydroxybutyrate, and acetone), serves as an alternative energy source. It has also been proposed that a ketogenic diet leads to systemic metabolic changes. Keeping in view the significant role of metabolic alterations in cancer, we hypothesized that a ketogenic diet may diminish glycolytic flux in tumor cells to alleviate cachexia syndrome and, hence, may provide an efficient therapeutic strategy. Results: We observed reduced glycolytic flux in tumor cells upon treatment with ketone bodies. Ketone bodies also diminished glutamine uptake, overall ATP content, and survival in multiple pancreatic cancer cell lines, while inducing apoptosis. A decrease in levels of c-Myc, a metabolic master regulator, and its recruitment on glycolytic gene promoters, was in part responsible for the metabolic phenotype in tumor cells. Ketone body-induced intracellular metabolomic reprogramming in pancreatic cancer cells also leads to a significantly diminished cachexia in cell line models. Our mouse orthotopic xenograft models further confirmed the effect of a ketogenic diet in diminishing tumor growth and cachexia. Conclusions: Thus, our studies demonstrate that the cachectic phenotype is in part due to metabolic alterations in tumor cells, which can be reverted by a ketogenic diet, causing reduced tumor growth and inhibition of muscle and body weight loss