Conférences 2018

Les Conférences : Année 2018

Invitation : Julie Dechanet-Merville – Immunoconcept Umr 5164

Thierry Walzer
Immunité innée dans les maladies infectieuses et autoimmunes – CIRI – Centre National de Recherche en Infectiologie – Lyon

 » NK cell maturation: from transcription factors to anti-tumor functions ».

Lundi 14 mai à 11h00
Salle de conférences CGFB – site de Carreire zone sud, université de Bordeaux

Natural Killer (NK) cells are innate lymphocytes with an important role in the early defense against intracellular pathogens and in the immune surveillance of tumors and metastases. We and others discovered in 2009 that NK cells underwent a program of maturation including at least three discrete stages. Over the years, we accumulated evidences that these three subsets have complementary functions and distributions. In particular, terminal maturation is associated with a major switch in the trafficking mode that is essential for the control of metastases. Moreover, we identified several transcription factors and molecular pathways that altogether control the maturation program. I will present recent unpublished data that shed light on the role of several factors including mTOR, S1P5, T-bet and Eomes in NK cell maturation.


Invitation : Frédéric Saltel – U1053

Lionel Larue
Director of the team « Normal and Pathological Development of Melanocytes
Acting Director CNRS UMR3347, INSERM U1021, Institut Curie
« Normal and pathological development of melanocytes: Advantages and inconvenient for the organism to be mutated or misregulated for β-catenin« 

Jeudi 19 avril à 11h00

Salle de conférences de l’IBGC – site de Carreire zone sud,
université de Bordeaux

The main goal of the laboratory is to decipher the molecular (Map-Kinase, PI3K and β-catenin) and cellular (migration, proliferation, apoptosis and invasion) mechanisms of the normal (establishment, homeostasis, and stem cells) and pathological (vitiligo, giant nevus and melanoma) development of melanocytes. The strategy is to exploit the high throughput correlative information generated around the world and in the laboratory. In parallel we focus on a keystone protein b-catenin. In both cases they establish original and relevant in vitro and in vivo mouse models, to better understand molecular heterogeneity and cellular plasticity, and to screen efficiently novel therapies with these models. Moreover, we study the regulation of b-catenin through the WNT, PI3K/PTEN and MAPK signalling pathways. We evaluate the importance of b-catenin interactants, such as cadherins, ICAT or LEF/TCF proteins and they assess the role of b-catenin in the regulation of transcription of targets including, MITF, BRN2, CSK or NEDD9. In conclusion, in order to achieve their goals, the laboratory constantly improves techniques, technologies and scientific concepts at the molecular, cellular and physiological levels.


Invitation : Milos Filipovic – IBGC CNRS 5095

Michel Toledano
Laboratoire Stress Oxydants et Cancer – Institut des Science du Vivant Frédérique Joliot
CEA-Saclay Gif-sur-Yvette France

«  Signaling by H2O2: specificity and physiological scope. »

Mardi 17 Avril à 11h00

Salle de conférences de l’IBGC – site de Carreire zone sud,
université de Bordeaux

Reactive oxygen species (ROS), which include hydrogen peroxide (H2O2), are toxic molecules that also operate in intracellular signaling. Both these effects are due to ROS relative high chemical reactivity, which enables them to oxidize biological molecules, thereby causing either oxidative damage, or modifying the activity of select regulatory proteins by covalent post-translation modification. Whereas the toxicity of ROS is intuitively perceived, their signaling function has been more difficult to grasp, owing to the paradox posed by the specificity required for signaling and the seeming indiscriminate reactivity of ROS. We will present data that contrast the high specificity that can be achieved in lower eukaryotes in H2O2 signaling with the seeming lack of specificity of the same signaling in higher eukaryotes. We will then tentatively propose clues to the H2O2 signaling conundrum of higher eukaryotes. One clue considers the role of another signaling molecule, H2S, and its intertwining with H2O2 signaling into another kind of specificity, and the other the physiological scope of these phenomena, and in particular their possible role in circadian regulation.

Invitation : Andreas Bikfalvi (Inserm U1029)

Curzio Rüegg
Professor and Chair of Pathology – Translational and experimental oncology
Department of Oncology, Microbiology, Immunology Faculty of Science and Medicine
University of Fribourg, Switzerland

“Type I interferon/IRF7 axis instigates chemotherapy-induced immunological breast cancer dormancy.”

Vendredi 23 mars à 11h
Salle de conférences de l’IBGC, site de Carreire zone sud, université de Bordeaux

Chemotherapy is widely used as a curative, adjuvant, and palliative treatment in breast cancer. While it is generally assumed that adjuvant chemotherapy works by killing residual or disseminated cancer cells, the observation that relapses can occur years to decades after treatment, suggests that other mechanisms, such as induction of dormancy and/or of an immune equilibrium may be involved. We recently demonstrated that breast cancer cells treated by chemotherapy induce a long-lasting protective T cell-dependent immune response that maintains cancer cells in a dormant state. Genome-wide gene expression analyses revealed as strong activation IRF7/type I interferon axis in the treated cells. This type I interferon response tips the balance from an immunosuppressive, MDSC-dominated response toward a T lymphocyte-mediated an anti-tumor response. This study demonstrates that chemotherapy can induce a state of sustained immunological dormancy and identifies type I IFNs as potential powerful therapeutic node to improve the efficacy of adjuvant chemotherapy.

Invitation : Isabelle Sagot – Inserm U 1035

Gilles Charvin
Institut de Génétique et de Biologie Moléculaire et Cellulaire – Illkirch

« On the mechanism of entry into replicative senescence in budding yeast »

Vendredi 16 mars à 11h00
Salle de conférences de l’IBGC – site de Carreire zone sud,université de Bordeaux

Budding yeast cells undergo about 25 divisions before entering senescence and eventually dying. Strikingly, daughters of aging mother recover a full replicative potential, a phenomenon known as rejuvenation. Whereas replicative aging in yeast has been described almost 60 years ago, its underlying mechanism remains obscure. In previous studies, we have designed a microfluidic chamber to trap individual mother cells and monitor their successive divisions from birth to death under the microscope and we have identified an abrupt senescence entry point (SEP), beyond which the cell cycle slows down in an irreversible manner. In this talk, after a long introduction about the diverse models proposed to explain replicative aging in yeast, I will describe our new results showing that an abnormal nucleolar activity is responsible for the loss of growth homeostasis observed after the SEP.  

Invitation : Jean-Max Pasquet – Inserm U 1035

Francis Lacombe
Hôpital Haut-Lévêque spécialiste de la cytométrie en flux et des nouvelles procédures en cytométrie en flux.

 » Unsupervised flow-cytometry advanced data analysis of normal and malignant human bone marrow. »

Mardi 6 mars à 14h00
Salle de conférences CGFB – site de Carreire zone sud, université de Bordeaux

The exploration of human bone marrow (BM) is an important tool to understand and diagnose diseases involving altered hematopoiesis. Although morphological identification of cells with distinctive features still remains the basis of these analyses, more sophisticated methods appeared to be necessary, in particular flow cytometry. To assess reproducibility of immunophenotyping analysis between different laboratories and different flow cytometers a new concept called Harmonemia was developed.

Many multidimensional software were designed for the analysis of big-data generated in mass cytometry (MS). Their application to classical multiparameter flow cytometry (MFC) is still seldom reported. FlowSOM, developed for MS within the Bioconductor open-source project, has been praised for its discriminative abilities and operator-friendly application. We combined FlowSOM and the Kaluza® software to analyze human bone marrow (BM) in MFC. Antibody panels adapted for the diagnosis of acute leukemias were applied to respectively 19 and 17 normal BM (NBM) samples. After normalization and merging, four FlowSOM reference minimal spanning trees (MST) were obtained, providing new ways of dissecting normal hematopoietic differentiation. Reference MST of NBM were then merged with diagnosis and follow-up files from patients with acute myeloblastic leukemia (AML) or acute lymphoblastic leukemia (ALL), for unsupervised concomitant analysis. This outlined the immunophenotypic heterogeneity of AML and ALL and allowed a fine delineation of minimal residual disease.

The combination of automated sophisticated multidimensional representation of numerous subsets and their in-depth analysis by classical manual tools of FCM analysis is a truly revolutionary approach. These versatile new tools open the way for a new era of classical flow cytometry analysis in hematological malignancies.


Invitation : Katia Boniface – Inserm U 1035

Jeremy Di Domizio
University Hospital of Lausanne CHUV, Lausanne, Switzerland

« Pathogenic role of interleukin (IL)-26 producing Th17 cells in the acute forms of psoriasis. »

Mardi 20 février à 14h00
Salle de conférences de la PGF – site de Carreire zone sud,université de Bordeaux

Chronic plaque-type psoriasis is a skin inflammatory disease driven by IL-17-producing Th17 cells. In addition to IL-17, Th17 cells in psoriasis produce other cytokines including interleukin (IL)-26, a member of IL-10 cytokine family. However, whether the production of IL-26 by Th17 cells plays a pathogenic role in psoriasis is unknown. By comparing IL-26 and IL-17 expression in psoriatic skin samples, we found that high IL-26 and low IL-17 were detected in acute forms of psoriasis, including erythrodermic and guttate-type, whereas low IL-26 and high IL-17 mainly associated with chronic plaque psoriasis. The dichotomy of IL-26 and IL-17 expression was confirmed in T cells infiltrating psoriatic skin lesions and circulating in the blood where IL-26 producing T cells and IL-17-producing T cells represented distinct cell populations within CXCR3CCR4+ CCR6+ Th17 cells. Finally, we assessed the pathogenic role of IL-26 in psoriasis by using IL-26-transgenic mice. Skin injury of IL-26 transgenic mice triggered an inflammatory response and a skin phenotype resembling psoriasis, suggesting a pathogenic role in the induction of the disease. Together, our findings indicate that IL-26 is expressed by a distinct subset of Th17 cells in acute forms of psoriasis, where it may drive the inflammatory process and disease development.

Invitation : Andreas Bikfalvi – Inserm U 1029


Gertraud Orend
INSERM U1109 – MN3T, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), France

« The extracellular matrix molecule tenascin-C promotes metastasis by several stromal and tumor cell autonomous mechanisms. »

Vendredi 2 février à 10h30
Salle de conférences de la Plateforme Génomique Fonctionnelle – site de Carreire zone sud, université de Bordeaux

The extracellular matrix molecule tenascin-C is highly expressed in cancer tissue where its abundance correlates with metastasis and worsened patient survival (1). We had developed the first stochastic tumor model with abundant and no tenascin-C, and demonstrated that tenascin-C promotes lung metastasis and multiple steps on the road to metastasis such as survival, migration, the angiogenic switch and non-productive angiogenesis through Wnt signaling employing repression of the Wnt signaling inhibitor Dickkopf 1 (2, 3). Tenascin-C may impact on tumor and stromal cells residing in so called tenascin-C matrix tracks in an autocrine (4) as well as paracrine manner (5).
Metastasis is a major cause of death in patients with cancer, and a better knowledge of the molecular mechanisms underlying metastasis may improve patient survival. Vascular invasions are prognostic factors for tumor metastasis, however the cellular and molecular organization of vascular invasions is not well characterised, nor is it clear how these features drive metastasis. We defined a universal cellular anatomy of vascular invasions and identify tenascin-C as a key component of these blood vessel invasions in cancer. We also demonstrate in a transgenic murine MMTV-NeuNT model of metastasis, engineered to control tenascin-C expression levels, that tenascin-C promotes endothelialization of vascular invasions, tumor cell survival, and dissemination of circulating tumor cells into lung parenchyma. We further show that tenascin-C induces epithelial-to-mesenchymal transition through TGF-b signaling promoting migration and survival (Sun et al., submitted).
Tenascin-C can also trigger tumor cell-autonomous signaling mechanisms explaining how tenascin-C promotes cancer cell migration. We demonstrate that as soon as tenascin-C is expressed it has an impact on tumor cell behaviour. In a murine xenograft model of advanced human osteosarcoma we demonstrated that tenascin-C and its receptor integrin α9β1 are essential for lung metastasis of tumor cells. We determined that activation of this pathway reduces tumor cell-autonomous expression of target genes for the transcription factor YAP and promoted amoeboid-like migration of cancer cells. This action of tenascin-C might have significance for cancer patients as in clinical specimens, a genetic signature comprising four YAP target genes represents prognostic impact (6).
Taken together, our results illuminate how tenascin-C in the tumor microenvironment promotes stromal and tumor cell autonomous effects thus promoting survival, angiogenesis, invasive migration and metastatic progression in a tumor and context dependent manner.

(1) Midwood et al., 2016, J Cell Sci, 29, 4321-4327
(2) Saupe et al., 2013, Cell Reports 5, 482-92
(3) Langlois et al., 2014, Oncotarget, 5, 10529-10545
(4) Spenlé et al., 2015, Cell Adh Migr, 9, 4 – 13
(5) Rupp et al., 2016, Cell Reports, 17, 2607-2619
(6) Sun et al., 2017, Cancer Res, doi: 10.1158/0008-5472

Invitation : Patrick Blanco – Immunoconcept Umr Cnrs 5164

Pascale Jeannin
« Immunité Innée et Immunothérapie » Centre de Recherche en Cancérologie Nantes-Angers |  Inserm U892

« IL-26: a novel soluble pattern recognition molecule with anti-viral properties. »

Mardi 30 janvier à 11h00
Salle de conférences de la PGF – site de Carreire zone sud,université de Bordeaux

IL-26 is a member of the IL-10 family, overexpressed in numerous chronic inflammatory disorders (rheumatoid arthritis, Crohn’s disease, psoriasis, vasculitis). Intriguingly, IL-26 acts on immune cells despite the absence of its originally described receptor (IL-10R2/IL-20R1).
IL-26 exhibits non-conventional physicochemical properties (amphipaticity and cationicity), conferring to IL-26 the capacity to bind nucleic acids. We have observed that IL-26 binds to extracellular DNA (released during massive cell death) and that DNA-IL-26 complexes are internalized by immune cells and activate them via DNA sensors. The presence of circulating IL-26-DNA complexes has been detected in patients with chronic inflammatory disorders. More recently, we have observed that IL-26 interacts with viral HCV RNA and, consequently, may interfere with HCV replication.
These studies identify IL-26 as a novel nucleic acid-binding PRM which exhibits potent anti-viral properties and amplifies chronic inflammatory responses.

Invitation : Christophe Grosset – Inserm U1035

Antonin Marchais
Département de cancérologie de l’enfant et l’adolescent
Equipe SPIAJA – Institut Gustave Roussy

« Characterization of phased siRNA biogenesis in mammals and plants from deep-sequencing data ».

Mardi 23 janvier 2018 à 11h00
Salle de conférences de l’IBGC – site de Carreire zone sud,université de Bordeaux

Over the past few years, important new aspects of small RNA biogenesis, maturation, editing and circulation have been described. These sophisticated processes vary with biological context and produce small RNAs with a wide range of sequence and spatial distributions. Statistical analysis of these variations from deep-sequencing data enables to identify the triggering biological perturbations; even at long distance from the initiator tissue if applied to circulating small RNAs.

In this scientific context, I will present our implementation of a versatile tool to detect and study phased biogenesis of viral derived siRNAs in mammals and endogenous siRNAs in Plants. Second half of the seminar will focus about our last work concerning new family of pseudogene derived siRNAs in Plants; their expression, tissue specificity and their probable role as translational repressor.

Invitation : Jean-Paul di Rago – IBGC Umr 5095

Thorsten Friedrich
Institute of Biochemistry, Albert-Ludwigs-Universität, Freiburg (Germany)

 « On the mechanism of respiratory complex I. »

Lundi 22 janvier à 11h00
Salle de conférences de l’IBGC – site de Carreire zone sud,université de Bordeaux

The energy-converting NADH:ubiquinone oxidoreductase, respiratory complex I, couples NADH-driven reduction of ubiquinone with a translocation of protons across the membrane. In doing so, it contributes to the generation of the proton motive force needed for energy-consuming processes. The L-shaped complex consists of a peripheral arm catalyzing electron transfer by means of one flavin mononucleotide and up to 10 iron-sulfur (Fe/S)-clusters, while the membrane arm is involved in proton translocation. Although high-resolution structures of the complex from various species are now available, the coupling of electron transfer with proton translocation is still not understood. In addition, complex I is a major source of reactive oxygen species (ROS) that may lead to DNA damage and are implicated in Parkinson’s disease and ageing. We generated an expression plasmid containing all 13 genes that encode the 13 different subunits constituting Escherichia coli complex I. Transformation of an E. coli strain that chromosomally lacks the genes of all membranous NADH dehydrogenases enables a fast characterization of any complex I mutant. Using this system we demonstrated that the Fe/S clusters are not a simple electron conducting wire. Instead, they regulate the intramolecular electron tunneling rates to synchronize this process with proton translocation and control NADH binding to prevent ROS-production by the complex. The molecular mechanism of enhanced binding of pyrimidine nucleotides was deciphered by the determination of the structure of the NADH oxidation module at up to 1.8 Å resolution in the reduced and oxidized states.

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