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SOX9 regulates ERBB signalling in pancreatic cancer development

Pancreatic cancer is one of the most aggressive cancers and a leading cause of cancer death. This cancer originates from lesions called Pancreatic Intraepithelial Neoplasia (PanIN) that can evolve into adenocarcinoma. A better understanding of the mechanisms driving the disease will contribute to better treatments.

The team of Patrick Jacquemin and Frédéric Lemaigre, in collaboration with the laboratory of Ilse Rooman, from the Garvan Institute, in Sidney, investigated the role of the transcription factor Sox9 in pancreatic cancer. They found that Sox9 is expressed at higher levels in a tumor subtype which is associated with better patient outcome and better response to therapy targeting the EGF receptor. High expression of Sox9 in human tumors correlates with high expression of several members of the EGFR/ERBB signaling pathway. Using mouse models, the team also demonstrated that Sox9 is essential for PanIN formation and is required for ERBB signaling activity.

By integrating data from patient samples and animal models, this work, recently published in the journal Gut, could help in the future to optimize selection of patients that may respond to therapy targeting the EGF signaling pathway.



LeSoirMag

LeSoirMag consacre un article à l'étude des télomères et consulte le Prof. Anabelle Decottignies : "L'effet de la longueur des télomères sur le comportement des cellules cancéreuses".

Changer notre mode de vie pour rallonger nos télomères - ces sortes de petits capuchons qui protègent nos chromosomes - et retarder ainsi notre vieillissement: tel est le défi qu'étudient aujourd'hui les scientifiques et dont les résultats seront publiés prochainement.

Cliquez ici pour l'article en entier.


ArGen-X

L'Institut de Duve et arGEN-X signent un contrat de recherche et de licence dans le domaine de la thérapie contre le cancer à base d'immunomodulateurs. Objectif ? Valider un résultat des recherches des Pr. Sophie Lucas et Pierre Coulie (UCL / Institut de Duve) dans ce domaine.

Cliquez ici pour plus d'infos.


Rentrée académique 2013 à Louvain-La-Neuve

Ce lundi 16 septembre 2013 a eu lieu la rentrée académique à Louvain-La-Neuve.

Christian de Duve et l'Institut ont été à l'honneur.

Sophie Lucas et Jean-François Collet les ont présentés tous deux avec brio.

Vous pouvez revoir toute la séance sur le lien suivant :
http://www.livestream.com/webtvcav/video?clipId=pla_49badd1d-26fc-4d48-9a04-2d4980143843
(Pour l'accès direct à la présentation de Sophie et Jean-François : 19 min 20 sec jusqu'à 28 min 05 sec)

Article du journal Le Soir


Evasion of antiviral innate immunity by Theiler’s virus L* protein through direct inhibition of RNase L.
Sorgeloos F, Jha BK, Silverman RH, Michiels T. PLoS pathog. 2013; 9(6):e1003474.

Theiler's virus is a murine picornavirus (same family as poliovirus) which has a striking ability to establish persistent infections of the central nervous system. To do so, the virus has to counteract the immune response of the host and particularly the potent response mediated by interferon. We observed that a protein encoded by Theiler's virus, the L* protein, inhibited the RNase L pathway, one of the best-characterized pathways mediating the antiviral IFN response. In contrast to previously identified viral antagonists of this pathway, L* was found to act directly on RNase L, the effector enzyme of the pathway. L* activity was found to be species-specific as it inhibited murine but not human RNase L. We confirmed the species-specificity and the direct interaction between L* and RNase L in vitro, using purified proteins. Acting at the effector step in the pathway allows L* to block RNase L activity efficiently. This suggests that RNase L is particularly important to control Theiler's virus replication in vivo. Another virus, mouse hepatitis virus (MHV), was recently shown to interfere with RNase L activation. Theiler's virus and MHV share a marked tropism for macrophages which may suggest that the RNase L pathway is particularly important in this cell type.

Viral proteins can interfere with the RNase L pathway at different levels.
Influenza virus protein NS1 prevents the detection of viral RNA by cellular sensors and thereby not only interferes with the RNase L pathway but also with PKR activation and with IFN production.
Theiler's virus L* protein acts at the effector step of the pathway. It directly interacts with RNase L. This ensures a strong inhibition of RNase L and outlines the importance of the latter enzyme in the defense against Theiler's virus.


Christian de Duve (October 2, 1917 - May 4, 2013)

We have the sad duty to announce the death of the founder and former director of our Institute.

Nous avons le triste devoir d'annoncer le décès du fondateur et ancien directeur de notre Institut.


Académie Royale de Belgique

Le 24 avril dernier, le Pr. Christian de Duve donnait une interview à l'Académie Royale de Belgique où il eut l'occasion de parler des progrès de la recherche mais aussi du Prix Nobel entre autres choses.

Cliquez ici pour accéder aux vidéos de l'entretien.


Prix InBev-Baillet Latour 2013

Cette année, le Prix InBev-Baillet Latour a été décerné, dans le domaine de la recherche clinique, aux Professeurs Miikka Vikkula et Laurence Boon pour leurs recherches sur les anomalies vasculaires. S.A.R. la Princesse Mathilde a remis le prestigieux prix aux chercheurs au cours d'une cérémonie réunissant quelques uns des plus grands scientifiques belges.

Consultez ici le communiqué de presse de la cérémonie.

Cliquez ici pour accéder à l'article du quotidien La Libre Belgique.
Cliquez ici pour accéder à l'article de RTLinfo.


19th J.F. Heremans Memorial Lecture

given by Prof. Marc Tessier-Lavigne
President, The Rockefeller University, New York

on Wednesday, November 28, 2012.

Title: Wiring the brain: molecular control of axon growth and pruning

Click on the link below to see the pictures of this event:
http://www.deduveinstitute.be/heremans_lecture_2012/index.html


Christian de Duve's latest book is out

"Sept vies en une, mémoires d’un Prix Nobel", published by Odile Jacob.

Click on the link below to see La Libre Belgique's column (January 4, 2013) "Christian de Duve raconte sa vie de chercheur":
http://www.lalibre.be/culture/divers/article/787880/christian-de-duve-raconte-sa-vie-de-chercheur.html


Telomere length regulates TERRA levels through increased trimethylation of telomeric H3K9 and HP1alpha

Chromosome ends are protected by very specialized structures called « telomeres » that are essential to ensure cellular proliferation. This is crucial for stem cells, like the ones residing in bone marrow. As we age, telomeres erode and chromosome end protection is compromised, leading to cellular ageing and, consequently, to organismal ageing. Telomeres are therefore commonly referred to as biological clocks and constitute a protective barrier against indefinite cellular proliferation, one of the hallmarks of cancer cells.

If normal cells are not able to proliferate indefinitely, why are cancer cells able to do so? Important studies unveiled the ability of cancer cells to efficiently synthesize telomeric DNA repeats through up-regulation of telomerase, the abundance of which is normally restricted to human embryonic cells. Hence, it turned out that telomerase may represent a novel attractive target in cancer therapy. The importance of telomeres and telomerase was recognized by the 2009 Nobel Prize in Medicine or Physiology.

Recent research in the field unveiled that telomere maintenance is not only a consequence of telomerase activity but requires additional players that, altogether, contribute to proper conformation of what is called “chromatin”. Chromatin is made of DNA and various DNA-associated proteins, including histones. Telomeric histones display specific marks that not only require the activity of histone-modifying enzymes but are also dependent on the presence of telomere-bound non-coding RNA molecules resulting from telomere transcription.

The study published by the group of Anabelle Decottignies brings new light on the regulation of telomeric RNA expression, going deeper into this aspect of human telomere biology. This work provides new insight into the mechanisms of telomeric chromatin regulation in cancer cells. In the future, a better understanding of telomeric chromatin regulation may help designing new anti-cancer therapies targeting telomeres.
Nature Structural & Molecular Biology 19, 948-956 (2012)


Prix Allard-Janssen 2012 décerné à Jean-Christophe Renauld

Le prix scientifique Allard-Janssen 2012 est décerné à Jean-Christophe RENAULD pour ses recherches qui consistent en l’identification des mécanismes par lesquels les cellules cancéreuses, en particulier les cellules leucémiques, acquièrent une capacité à proliférer de façon indépendante des facteurs de croissance.

Né en 1963, Jean-Christophe Renauld est docteur en médecine de l’UCL; depuis 1988 chercheur à la Branche de Bruxelles du Ludwig Institute for Cancer Research; depuis 2010 professeur extraordinaire à l’UCL et cotitulaire du cours d’immunologie pour les étudiants de la  Faculté de Médecine; lauréat de plusieurs prix comme le prix international Interbrew-Baillet-Latour de la santé en 2000 et le prix Pfizer en 2008.


Role of the ductal transcription factors HNF6 and Sox9 in pancreatic acinar-to-ductal metaplasia

Pancreas sustains exocrine functions that are exerted by the acinar cells which produce and secrete digestive enzymes, and the ductal cells which line ducts that drain the secretions to the intestine. When pancreas is affected by inflammation (pancreatitis) acinar cells acquire the shape and structure of duct cells, a lesion called acinar-to-ductal metaplasia (ADM). Pancreatitis is a risk factor for pancreatic adenocarcinoma (PA), a deadly cancer of the pancreas. Mouse models suggest that acinar cells are the cell type at the origin of PA and consequently, that ADM is a precursor lesion of this cancer. Until now, gene regulators controlling ADM have not yet been identified.

The team of Patrick Jacquemin and Frédéric Lemaigre investigated the involvement of HNF6 and Sox9, two transcription factors normally expressed in ductal cells, play a role in development of ADM. The team found that both factors are detected in human metaplastic acinar cells associated with pancreatitis and PA. Sox9 is also expressed in invasive PA cells. Forced expression of HNF6 in acinar cells induces metaplasia, and deletion of HNF6 and Sox9 inhibits development of ADM. The team further showed that HNF6 and Sox9 activate expression of genes typically expressed in duct cells while repressing acinar gene expression in metaplastic acinar cells. These results are published in the journal "Gut".

Beyond these results, these findings indicate that HNF6 and Sox9 are functional biomarkers of ADM. The two factors may become targets for developing drugs that inhibit progression of preneoplastic stages of PA in families with genetic predisposition to pancreatitis or PA. This work also suggests that metaplastic processes found in other organs are controlled by ectopic expression of transcription factors.


Chaire Francqui 2011-2012 aux FUNDP à Emile Van Schaftingen

Leçon du 28 février 2012: Leçon inaugurale

Le métabolisme intermédiaire dans l’ère génomique : l’apport des génomes dans la découverte de nouvelles enzymes.

Jusqu’avant l’ère ‘génomique’, l’élucidation du métabolisme intermédiaire se basait principalement sur (1) la découverte de métabolites, suivie par (2) la découverte d’enzymes formant ou utilisant ces métabolites, et (3) par l’identification des gènes codant ces enzymes.  Cette approche a bien fonctionné pour découvrir tous les éléments des voies métaboliques (quantitativement) majeures.  Le séquençage des génomes permet la découverte d’enzymes dont on postulait l’existence, mais qu’on n’avait jamais pu découvrir, ou, mieux encore, de découvrir des enzymes dont on ne soupçonnait pas l’existence.  Le génome humain code ainsi des centaines d’enzymes ‘putatives’, sans doute impliquées dans le métabolisme intermédiaire et dont nous ne connaissons pas la fonction précise. Trouver des stratégies pour identifier leur fonction représente un défi majeur. 

Leçon du 6 mars 2012: Une nouvelle vision de la spécificité enzymatique : la répartition de métabolites fautifs !

Leçon du 13 mars 2012: La réparation des protéines, un phénomène sous-estimé et impliquant des réactions inattendues.

Leçon du 20 mars 2012: La glucokinase, une enzyme surprenante et un acteur central du métabolisme glucidique chez l’homme.

Leçon du 27 mars 2012: Le fructose-2,6-biphosphate et autres molécules de signalisation métabolique.

Programme détaillé : http://www.fundp.ac.be/facultes/medecine/


Christian de Duve's latest book is out

"De Jésus à Jésus en passant par Darwin", published by Odile Jacob.

Click on the link below to see La Libre Belgique's column (October 15, 2011) "de Duve en appelle au message de Jésus":
http://www.lalibre.be/culture/livres/article/692061/de-duve-en-appelle-au-message-de-jesus.html


Hepatic stem cells

Embryonic Ductal Plate Cells Give Rise to Cholangiocytes, Periportal
Hepatocytes, and Adult Liver Progenitor Cells

The main cell types in the liver are the hepatocytes, which exert most metablic functions of the liver, and the cholangiocytes, which line ducts through which bile flows to the intestine. In the embryonic liver, it was considered that a cell population –called ductal plate cells- located around the branches of veins constituted the progenitors of the cholangiocytes, whereas a distinct cell population was considered to give rise to the hepatocytes.
The team of Frederic Lemaigre now used a genetic labeling technique which enables to mark specifically the ductal plate cells in the mouse embryonic liver, and then to follow the fate of the marked cells after birth and in the adult (Carpentier et al. Gastroenterology 2011). It was found that the ductal plate cells give rise to cholangiocytes, as expected, but also to a subpopulation of hepatocytes, thereby revealing that the ductal plate cells have wider differentiation potential than previously thought.
Moreover, the liver has the capacity to regenerate after injury. In some conditions, such regeneration depends on so-called adult hepatic stem cells, the origin of which being debated. The team has shown, using the same genetic labeling technique, that the ductal plate cells give rise to the adult hepatic stem cells, which can now be traced and investigated during liver regeneration.


Orientation-specific signalling by thrombopoietin receptor dimers

(Thrombopoietin Receptor Signals from Different Dimeric Orientations to Promote Physiologic and Pathologic Blood Formation)

Thrombopoietin (Tpo) is a cytokine produced by the liver that is critical for regulation of the formation of platelet cells, the small anucleated blood cells that derive from the cytoplasm of megakaryocytes and that prevent bleeding upon injury. Tpo also regulates the numbers of hematopoietic stem cells and other myeloid cells. The group of Stefan Constantinescu described in 2006 and 2010 mutations around the transmembrane domain of TpoR that induce different levels of receptor activation and myeloproliferative diseases in vivo (Staerk et al., Blood 2006 107(5):1864-71; Pecquet et al., Blood 2010 115(5):1037-48).

The team thought to probe whether this receptor could actually signal from several different individual dimeric conformations. To this end short (28 amino-acid) dimeric peptides were genetically fused upstream of the transmembrane domain of TpoR, in the place of the extracellular domains. A set of seven distinct dimers was obtained, which scanned all possible dimeric interfaces.  The laboratory has now shown that only one dimeric orientation of TpoR is totally inactive, while others promote either normal platelet formation, myeloproliferative disorders, and, surprisingly, in one conformation the receptor induces a myelodysplastic disorder resembling another human disease (Staerk et al., EMBO J, 2011, In Press Sep 2. doi: 10.1038/emboj.2011.315.). Thus, subtle differences in cytokine receptor dimerization provide a new level of regulation of function, that is relevant for disease. This property could be exploited by partial agonists, antibodies or small molecules.


Interview with Christian de Duve at the Lindau Nobel Laureate Meeting, 2011

In this Scientific American podcast Steve Mirsky interviews 1974 Nobel laureate of physiology and medicine Christian de Duve about going from a cell biologist to a theorist on evolution and the origin of life (duration 21.25 min).

http://www.scientificamerican.com/podcast/episode.cfm?id=science-legend-christian-de-duve-11-09-09


Guido Bommer obtains a permanent FNRS position

Guido Bommer arrived at the de Duve Institute at the end of 2008 with the support of a Brains-Back-to-Brussels grant from the Region Bruxelles Capitale. He is leading a small research group investigating the role of small regulatory RNAs in different human diseases. Starting from October 2011 he will be supported by a permanent position of the FNRS.


Interferon-lambda protects epithelia against viral infection

Interferons (IFNs) are cytokines that are produced by virus-infected cells. They act on the receptor expressed by neighboring cells to transmit infection alert signals. After stimulation by IFN, cells express a series of genes that make them more resistant to subsequent viral infection.
IFN-lambda was discovered recently and appeared to have very similar activities as the previously known IFN-alpha/beta.

In a previous work, it was found by the team of Thomas Michiels that IFN-lambda acted almost exclusively on epithelial cells, in contrast to IFN-alpha/beta that acts on almost any cell type, suggesting that IFN-lambda evolved as a protection of mucosa against pathogen invasion (Sommereyns et al., PLoS Pathog. 2008 Mar 14;4(3):e1000017....). Now, work performed by the teams of Mathias Hornef (Univ. Hanover) and Peter Stäheli (Univ. Freiburg), in collaboration with our Institute have confirmed the view that IFN-lambda acted as a protection of mucosal surfaces. This work recently published in PNAS showed that IFN-lambda acts in a non-redundant way, to protect the gastro-intestinal epithelium against infection by rotavirus (Pott et al. Proc Natl Acad Sci U S A. 2011,108: 7944-9).


Lauréats Welbio à l'Institut de Duve

Jean-François COLLET
Comprendre les mécanismes rédox impliqués dans le repliement et la réparation des protéines dans l’enveloppe cellulaire: une étape vers le développement de nouveaux antibiotiques

Pierre COULIE
Exploration et analyse d’interactions inefficaces entre des cellules cancéreuses et des lymphocytes T humains

Benoît VAN den EYNDE
Etude des mécanismes d’apprêtement des antigènes et caractérisation de nouveaux sous-types de protéasome

Pierre van der BRUGGEN
Le rôle des galectines dans la régulation de la réponse immunitaire

Emile VAN SCHAFTINGEN
La réparation de métabolites fautifs, une nouvelle vue de la spécificité enzymatique

Miikka VIKKULA
Identification de nouveaux gènes lymph/angio-géniques en utilisant le séquençage à haut débit.