Laminin α5 guides tissue patterning and organogenesis

Laminins (LM) are extracellular matrix molecules that contribute to and are required for the formation of basement membranes. They participate in the modulation of epithelial/mesenchymal interactions and are implicated in organogenesis and maintenance of organ homeostasis. Among the LM molecules, the LM α5 chain (LMα5) is one of the most widely distributed LM in the developing and mature organism. Its presence in some basement membranes during embryogenesis is absolutely required for maintenance of basement membrane integrity and thus for proper organogenesis. LMα5 also regulates the expression of genes important for major biological processes, in part by repressing or activating signaling pathways, depending upon the physiological context

Quantitative proteomics identify Tenascin-C as a promoter of lung cancer progression and contributor to a signature prognostic of patient survival

The extracellular microenvironment is an integral component of normal and diseased tissues that is poorly understood owing to its complexity. To investigate the contribution of the microenvironment to lung fibrosis and adenocarcinoma progression, two pathologies characterized by excessive stromal expansion, we used mouse models to characterize the extracellular matrix (ECM) composition of normal lung, fibrotic lung, lung tumors, and metastases. Using quantitative proteomics, we identified and assayed the abundance of 113 ECM proteins, which revealed robust ECM protein signatures unique to fibrosis, primary tumors, or metastases. These analyses indicated significantly increased abundance of several S100 proteins, including Fibronectin and Tenascin-C (Tnc), in primary lung tumors and associated lymph node metastases compared with normal tissue. We further showed that Tnc expression is repressed by the transcription factor Nkx2-1, a well-established suppressor of metastatic progression. We found that increasing the levels of Tnc, via CRISPR-mediated transcriptional activation of the endogenous gene, enhanced the metastatic dissemination of lung adenocarcinoma cells. Interrogation of human cancer gene expression data revealed that high TNC expression correlates with worse prognosis for lung adenocarcinoma, and that a three-gene expression signature comprising TNC, S100A10, and S100A11 is a robust predictor of patient survival independent of age, sex, smoking history, and mutational load. Our findings suggest that the poorly understood ECM composition of the fibrotic and tumor microenvironment is an underexplored source of diagnostic markers and potential therapeutic targets for cancer patients

Proteolytic and opportunistic breaching of the basement membrane zone by immune cells during tumour initiation.

Cancer-related inflammation impacts significantly on cancer development and progression. From early stages, neutrophils and macrophages are drawn to pre-neoplastic cells in the epidermis, but before directly interacting, they must first breach the underlying extracellular matrix barrier layer that includes the basement membrane. Using several different skin cancer models and a collagen I-GFP transgenic zebrafish line, we have undertaken correlative light and electron microscopy (CLEM) to capture the moments when immune cells traverse the basement membrane. We show evidence both for active proteolytic burrowing and for the opportunistic use of pre-existing weak spots in the matrix layer. We show that these small holes, as well as much larger, cancer cell-generated or wound-triggered gaps in the matrix barrier, provide portals for immune cells to access cancer cells in the epidermis and thus are rate limiting in cancer progression

Abnormal Wnt and PI3Kinase Signaling in the Malformed Intestine of lama5 Deficient Mice

Laminins are major constituents of basement membranes and are essential for tissue homeostasis. Laminin-511 is highly expressed in the intestine and its absence causes severe malformation of the intestine and embryonic lethality. To understand the mechanistic role of laminin-511 in tissue homeostasis, we used RNA profiling of embryonic intestinal tissue of lama5 knockout mice and identified a lama5 specific gene expression signature. By combining cell culture experiments with mediated knockdown approaches, we provide a mechanistic link between laminin α5 gene deficiency and the physiological phenotype. We show that laminin α5 plays a crucial role in both epithelial and mesenchymal cell behavior by inhibiting Wnt and activating PI3K signaling. We conclude that conflicting signals are elicited in the absence of lama5, which alter cell adhesion, migration as well as epithelial and muscle differentiation. Conversely, adhesion to laminin-511 may serve as a potent regulator of known interconnected PI3K/Akt and Wnt signaling pathways. Thus deregulated adhesion to laminin-511 may be instrumental in diseases such as human pathologies of the gut where laminin-511 is abnormally expressed as it is shown here

laminin-511, actor of inflammation and of tumoral progression in the intestine?

La laminine-511 (a5b1y1), élément de la matrice extracellulaire, fait partie des molécules médiatrices des interactions épithélio-mésenchymateuses qui contrôlent le développement intestinal puis le renouvellement cellulaire dans l'organe mature. Une rupture de l'homéostasie de l'ensemble de ces mécanismes est centrale dans les maladies inflammatoires chroniques de l'intestin (MICI) qui, dans une certaine proportion, peuvent dégénérer en cancer colorectal. Ce travail de thèse a permis de démontrer que la chaîne a5 de laminine, caractéristique de la laminine-511, pouvait d'une part réguler l'expression de gènes cibles importants dans les fonctions biologiques majeures des cellules intestinales et d'autre part était capable de réprimer ou d'activer deux voies de signalisation, Wnt et PI3K/Akt, suivant le contexte physiologique. Dans le contexte pathologique particulier des MICI, j ai pu définir la composition en laminines de la lame basale dans des segments pathologiques issus d'exérèses chirurgicales de côlons de patients atteints de maladie de Crohn ou de rectocolite hémorragique. De façon très intéressante, des glandes atypiques y ont été trouvées, délimitées par une lame basale enrichie en chaînes a1 et a5 de laminines et caractérisées par une accumulation nucléaire de la protéine p53, suppresseur de tumeur. J ai pu définir, par des expériences in vitro, une chronologie d'activation montrant que la protéine p53 était capable de stimuler l'expression endogène de la chaîne a1 de laminine. J ai également pu modéliser les résultats obtenus chez l'humain par des inductions chimiques d'inflammation et de tumorigenèse associée grâce à des modèles de souris transgéniques sur-exprimant soit la chaîne a1 soit la chaîne a5 dans l'épithélium intestinal, modèles établis par l'équipe. Les dérégulations des laminines qui ont été observées peuvent jouer un rôle important dans la rupture de l'épithélium, l'inflammation et les mécanismes de réparation qui leur sont inhérents ou dans la progression des MICI en cancer.The laminin-511 (a5b1y1), key element of the extracellular matrix, mediates the epithelialmesenchymal interactions controlling the intestinal development and the cell renewal in the mature organ. A deregulation of the mechanisms implied in the homeostasis is obvious in inflammatory bowel diseases (IBD). IBD can in some cases degenerate into colorectal cancer. My present work demonstrates that the a5 chain, characteristic of the laminin-511 molecule, regulates the expression of target genes important for major biological functions of the intestinal cells as well as is able to repress or activate two signaling pathways, Wnt and PI3K/Akt, according to the physiological context. In the particular context of IBD, I could define the laminin composition of the basement membrane in pathological samples from surgical resection of colon from patients with Crohn s disease or Ulcerative colitis. Interestingly, atypical glands are also found in these samples. These glands are encircled with a basement membrane enriched in laminin a1 and a5 chains and are characterized by a nuclear accumulation of p53, a tumor suppressor. By in vitro experiments, I have defined a chronology of activation showing that the p53 protein is able to stimulate the endogenous expression of the laminin a1 chain. I could mimic the results obtained in humans by triggering inflammation and inflammation-associated tumorigenesis chemically to transgenic murine models overexpressing either the laminin a1 or a5 chain, models that were previously established in the team. The laminin-observed deregulations could play an important role in the epithelium rupture, the inflammation and the inherent repair mechanisms, as well as in the progression of IBD into cancer

Das Kräfteverhältnis der Gliedstaaten im Gesamtgefüge des Bundesstaates : unter besonderer Berücksichtigung des Konzepts des schweizerischen Zweikammersystems

Switzerland's political legitimacy rests on two pillars – federalism and democracy. The relationship between the two is highly complex and has developed very unevenly over the past 150 years. When the Swiss Confederation was founded, the cantons were regarded as the central pillars of the political system. In this respect they have now been superseded by the federal government. Demographic developments have led to a situation in which the political weight of the town cantons is not adequately reflected, particularly in the Council of States, although the majority of the population lives in these cantons. The central concern of this book is to identify the tensions and contradictions between federalism and the democratic principle and, at least in certain areas, to attempt a reconciliation between these two principles. The author analyses the fundamental problem of the equal treatment of regional representative bodies within a federal system and suggests possible alternative models. The study shows how equal treatment of member states in Swiss constitutional law has been realised, focusing particularly on constitutional history. The position of the Council of States in the Swiss constitutional system and the bicameral system in its present form are analysed in detail and critically. In particular the author examines the question of whether the small chamber actually is the repository of federalist philosophy that it is often claimed to be. The issue of whether the Swiss bicameral system in its present form is justifiable and viable in the modern world is also explored. The author proposes measures that take account both of the history of the Swiss constitutional system and of the requirements of the future

Guide du calcul en mécanique: valider le comportement des systèmes techniques

Ce guide couvre l’essentiel des programmes de la Première STI2D aux sections de BTS pour les compétences liées à la mécanique. Pour prendre en compte les nouveautés pédagogiques, cette nouvelle édition évolue vers des systèmes « grand public » (robotique humanoïde, cycle trainer, power-ball…) ou des systèmes liés au développement durable(éolienne, scooter électrique…). Points forts - Un guide qui tient compte des orientations du nouveau programme de STI2D : - systèmes vibratoires ; - accéléromètres, effet gyroscopique ; - développement de l’énergétique. - Les disciplines Génie mécanique/Génie électrique sont décloisonnées: - introduction de dispositifs pluri-techniques ; - présentation d’interfaces liant la partie opérative à la partie commande ; - introduction de la conversion de l’énergie électrique en énergie mécanique et réciproquement, étude comportementale, point de fonctionnement, définition des grandeurs associées. - Le caractère expérimental, et l’approche inductive des lois sont soulignés : introduction de dispositifs expérimentaux inédits en énergétique et en résistance des matériaux. - Un outil efficace pour renforcer la méthodologie de résolution des problèmes. - Un guide ressources en travaux pratiques, travaux dirigés et en démarche de projet