Conférences 2017

Les Conférences : Année 2017

Invitation : Bruno Cardinaud – U1218

Kévin Lebrigand
UCAGenomiX, Functional Genomics Platform of Nice-Sophia-Antipolis,
CNRS, IPMC, Université Côte d’Azur

“Single-cell RNA sequencing: the Nice experience.”

Mercredi 22 novembre à 11h00
Salle de conférences de la Plateforme Génomique Fonctionnelle –

Site de Carreire zone sud, université de Bordeaux

Elected in 2013 “method of the year” by the journal Nature Methods, single cell sequencing now allows profiling of gene expression at the level of individual cells (scRNA-seq). Thanks to recent technical improvements in single cell manipulation and library preparation, scRNA-seq has become a powerful tool for high-throughput and high-resolution transcriptomic analysis. It is now possible to define the transcriptomes of thousands of single cells and to establish the molecular identity card for each cell in a cell population. In this talk, i will cover the recent scRNA-seq developments of the UCAGenomix platform in Nice including results obtained with our recently acquired 10xGenomics system which allows simultaneous profiling of thousands of cells.

Invitation : Harry Wodrich – Cnrs Umr 5234

Johan Garaude
INSERM U1211 | Laboratoire Maladies Rares – Génétique et Métabolisme

“Innate Immune regulation of mitochondrial respiratory chain during bacterial infection”

Mardi 17 octobre à 11h00
Salle de conférences de l’IBGC – site de Carreire zone sud,
université de Bordeaux

Metabolic reprogramming has recently emerged as a major feature of innate immune cells. At the core of immune cell metabolic reprogramming is the mitochondrion, a bioenergetic organelle that also serves as an immune signaling platform. While much effort has been made to dissect metabolic fluctuations during myeloid cell activation through pattern recognition receptors, the precise role of the mitochondrial respiratory chain is still poorly defined. Our work thus aims at unraveling the structural and functional adaptations of the respiratory chain and their relevance for innate immune cells contribution to antibacterial immunity. We specifically assess the connection between innate immune receptors engagement by microbial products and the electron transport chain regulation. In turn, we evaluate the innate immune consequences of respiratory chain dysfunctions.

Invitation : Bertrand Daignan-Fornier – IBGC UMR 5095

Yann Desfougères
Laboratory for Molecular Cell Biology (LMCB)
Medical Research Council, University College London

“Phosphate homeostasis and energy metabolism in eukaryotes”

Jeudi 28 septembre à 11h00

Salle de conférences de l’IBGC – site de Carreire zone sud

Adenosine triphosphate (ATP) is the universal biological energy currency. Its cellular concentration is tightly regulated and depends on rates of glycolysis, oxidative phosphorylation, and obviously on phosphate availability. How is phosphate concentration regulated as a function of the cell’s demands? Inositol pyrophosphates, described as metabolic messengers, have been proposed as candidates to orchestrate phosphate homeostasis and energy metabolism. However, most of our current knowledge comes from studies in the yeast Saccharomyces cerevisiae and many of the genes identified in yeast defining the “PHOsphate pathway” are not conserved in other eukaryotes. We have established the social amoeba Dictyostelium discoideum as an alternative model to study phosphate homeostasis in eukaryotes and to investigate the intricate relationship between inorganic phosphate (Pi), inositol polyphosphates (InsPs), and inorganic polyphosphate (polyP).

In our quest to define the complex enzymology of amoeba inositol phosphate synthesis, we discovered a new activity for the highly conserved inositol-tetrakisphosphate 1-kinase (ITPK1). This opens a new perspective to understand the function of the highly phosphorylated inositol phosphates that appears to be more complex than previously thought. We are also investigating how inorganic polyphosphate is produced, where it is stored and why it is important during amoeba development. Our recent results show that polyP is secreted during starvation, that this process requires the membrane fusion machinery, and that polyP is degraded after secretion.

Invitation : Isabelle Sagot – IBGC CNRS 5095

Marie-Emilie Terret
CIRB, Collège de France, UMR7241/U1050, PSL, 75005 Paris, France.

“Cortical tension participates in chromosome alignment in mouse oocytes.”

Vendredi 22 septembre à 11h00

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

Cortical tension participates in chromosome alignment in mouse oocytes.

Isma Bennabi1, Agathe Chaigne2, Marie-Hélène Verlhac1 and Marie-Emilie Terret1.
1CIRB, Collège de France, UMR7241/U1050, PSL, 75005 Paris, France.
2MRC Laboratory for Molecular Cell Biology, UCL, London WC1E 6BT, UK.

In oocytes, cells lacking canonical centrosomes, two F-actin networks replace astral microtubules for spindle positioning. They exert forces on the spindle sufficient to embark it to the cortex, leading to an asymmetric division in size. The first actin mesh is cytoplasmic and includes an actin cage surrounding the meiotic spindle. The second one consists of a cortical actin thickening that promotes a decrease in cortical tension and cortex softening. We have shown previously that this change in cortex mechanics controls the geometry of oocyte (and embryo) division since oocytes presenting too stiff or too soft cortices divide symmetrically (1-3). Interestingly, human and mouse oocytes developmental potential is accurately predicted by their cortical tension within hours after fertilization: if they are too stiff or too soft, embryos will cease development (4). Our goal is to understand the origin of early developmental failure due to cortical tension defects. Our results point towards a role of cortical tension in chromosome alignment in mouse oocytes. We show that aberrant cortical tension, a frequent defect in a normal population, could lead to chromosome alignment defects in oocytes, potentially contributing to oocyte predisposition to chromosome segregation defects, a leading cause of aneuploidy in embryos.

  1. Chaigne A et al. A soft cortex is essential for asymmetric spindle positioning in mouse oocytes. Nat Cell Biol 15 : 958-66 (2013).
    Chaigne A et al. A narrow window of cortical tension guides asymmetric spindle positioning in the mouse oocyte. Nat Commun 6, 6027 (2015).
  2. Chaigne A et al. F-Actin Mechanics Control Spindle Centring In The Mouse Zygote. Nat Commun 7,10253 (2016).
  3. Yanez LZ et al. Human oocyte developmental potential is predicted by mechanical properties within hours after fertilization. Nat Commun 7, 10809 (2016).

 

Invitation : Milos Filipovic – IBGC CNRS 5095

 Matt Whiteman
Professor of Experimental Therapeutics
University of Exeter Medical School – Great Britain

 “Therapeutic potential of mitochondria-targeted hydrogen sulfide.”

Jeudi 6 juillet 2017 à 14h00

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

 Several mitochondrial functions have recently been found to be regulated by hydrogen sulfide (H2S) such as mitochondrial respiration, ATP synthesis, apoptosis and inflammation Mitochondria are also capable of generating H2S via the enzyme via 3-mercaptopyruvate sulphurtransferase (3-MST). Oxidative stress results in the inhibition of mitochondrial H2S synthesis and/or depletion of mitochondrial H2S and the translocation of the cytosolic enzyme cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) to mitochondria resulting in further mitochondrial H2S synthesis. Cellular and mitochondrial H2S levels are also depleted, or H2S synthesis is inhibited, in vascular disorders such as hypertension, COPD, heart failure, myocardial infarction and diabetes etc., and pharmacological inhibition or genetic removal of CSE exacerbates the detrimental effects of oxidative stress (e.g. exacerbated mitochondrial dysfunction), on inflammation, heart and blood vessel damage in atherosclerosis, hypertension and pre-eclampsia. Conversely, ‘H2S replacement’ with either crude sulfde salts such as Na2S or slow release donor compounds such as GYY4137 prevents/reverses mitochondrial damage in these models. These studies have suggested that mitochondrial generation of H2S is crucial for cell survival and control of inflammation. As such, approaches to ‘replenish’ lost H2S offer a novel and viable therapeutic approach for the treatment of disease. However, Na2S (and NaSH) instantly dissociate at physiological pH to generate an immediate bolus of H2S at the site of application severely limiting the selective delivery of H2S to target tissues and generation of H2S from GYY4137 very slow and inefficient and its high water solubility may limit cellular permeability/uptake. Neither approach is capable of selectively delivering very low concentrations of H2S to mitochondria. We have therefore developed a series of novel mitochondria-targeted H2S donors. Mitochondria-targeting was achieved using triphenylphosphonium (TPP+) and novel peptides, and sulfide generation using hydroxythiobenzamide (HTB), anethole dithiolethione (ADT-OH) or a novel donor (RT-02). In vitro ‘cytoprotection’ screening experiments were performed in a variety of cells exposed to biological oxidants (e.g. H2O2, 4-HNE, peroxynitrite, glucose oxidase, hyperglycaemia, UV light etc.). Mitochondrial and cellular ‘ROS’ production, mitochondrial and cytoplasmic protein and DNA damage, ATP synthesis and cellular bioenergetics (Seahorse) were also determined. From these studies two lead compounds were identified, AP39 (containing ADT-OH), AP123 (containing HTB) and RT-01 (containing RT-02). In each assay AP39, RT-01 and AP123 were shown to confer greater cytoprotection and reduction in oxidative stress and mitochondrial damage than GYY4137 (or Na2S) at substantially lower concentrations (e.g. 0.3–100 nM c.f. >200 µM GYY4137). In animal models of hypertension, cardiac arrest, myocardial, burn injury and renal ischaemia-reperfusion, low dose mitochondrial donors (e.g. 7-500 µg/kg c.f. up to 500 mg /kg GYY4137) exerted significant cardio- and neurovascular. The mechanisms for these observation swill be discussed and collectively, these studies strongly suggest that selective delivery of H2S to mitochondria may represent a novel therapeutic approach to treat human disease.

 

Invitation : Alain Taïeb – Inserm U 1035

Jean Krutmann
IUF – Leibniz Research Institute for Environmental Medicine

IUF – Leibniz-Institut für umweltmedizinische Forschung gGmbH
Düsseldorf

“The AHR as a sensor of environmental stress to skin.”

Mardi 4 juillet à 14h00
Salle de conférences de la Plateforme Génomique fonctionnelle – site de Carreire zone sud, université de Bordeaux

Chronic exposure to solar radiation is a major cause of environmentally-induced skin aging, which is therefore traditionally referred to as photoaging. We and others have shown that within the solar spectrum, wavelengths in the Ultraviolet (UV) B and A range, but also visible light and near infrared radiation can cause skin aging (reviewed in 1). More recent studies suggest, however, that extrinsic skin aging is more than photoaging and, in particular, that traffic related air pollution independently contributes to skin aging. In epidemiological studies chronic exposure to ambient particulate matter (PM) as well as nitrogen oxide (NO2) was found to be significantly associated with more pigment spots on cheeks of elderly Caucasian as well as Han Chinese (2,3). This association was modified by genetic variants. Accordingly, we observed a significant interaction between air pollution and Arylhydrocarbon Receptor (AHR) /Arylhyrocarbon Receptor Repressor genetic risk scores on cheek lentigines. Women with a high genetic risk score for AHR/AHRR develop 52 % more lentigines on the cheeks after an increase of 4.45 μg/m3 (IQR) in PM2.5 and 36 % more lentigines after an increase of 5.54 μg/m3 (IQR) in PM10, whereas there was no association in women with a low risk score. We thus show that gene environment interactions are involved in environmentally-induced skin aging in general and air pollution-induced lentigines formation in particular. These results also indicate that AHR signaling is involved in environmentally-induced skin aging. In line with this assumption are in vitro studies in which topical application of ambient relevant Diesel Exhaust Particles caused AHR-dependent gene transcription in ex vivo human skin models. Interestingly, AHR signaling may also be induced in skin by UVB irradiation (4) and critically contribute to photocarcinogenesis. In contrast to AHR +/+ mice, AHR -/- animals developed 50 % less skin tumors in a chronic UVB irradiation study. In subsequent experiments we found that this procarcinogenic action of AHR signaling is due to a negative regulation of DNA damage responses in UVB irradiated keratinocytes which critically involves the interaction of AHR with p27 (5). Taken together these studies suggest that AHR might be a molecular target for the prevention of extrinsic skin aging / skin cancer (6). We have therefore recently developed a competitive AHR antagonist which can be topically applied to human skin and inhibit UVB radiation as well as air pollution-induced AHR activation in human skin cells in vitro and in vivo (7).

 

Invitation : Cécile Contin-Bordes – ImmunoConcept CNRS UMR 5164

Eric Vivier
Centre d’Immunologie de Marseille-Luminy, Aix Marseille Univ, CNRS, INSERM, 13288 Marseille, France Service d’Immunologie, Hôpital de la Timone, Assistance Publique-Hôpitaux de Marseille, Marseille, France

“Innate lymphoid cells: from discovery to therapy.”

Mardi 20 juin à 11h00

Salle de conférences de la Plateforme Génomique Fonctionnelle – site de Carreire zone sud,université de Bordeaux

Less than ten years after their initial description, the comprehension of innate lymphoid cells (ILCs) biology is rapidly improving. ILCs can be classified on the basis of their similarity to T cell subsets in terms of their cytokine production and expression of key transcription factors. Various immunological functions of ILCs have been described, and increasing numbers of studies have implicated these cells in immune responses. Using models of selective ILC depletion and studying cohorts of patients with severe ILC deficiency, we could show that ILCs appear redundant for protective immunity in conditions of modern hygiene and medicine, if T and B cell functions are preserved. However, ILCs appear to be critical for the onset or the maintenance of several inflammatory disorders such as asthma, chronic rhinosinusitis, atopic dermatitis, inflammatory bowel diseases, psoriasis, systemic or organ-specific inflammatory and autoimmune diseases. Future directions in the field will be discussed, together with potential avenues of treatment.

Recent research advances have also shed new light on the role the immune system plays in advanced-stage cancer. Immunotherapies have terribly increased in numbers and in diversity. Among immune effectors suitable for manipulation, Natural Killer (NK) cells are of particular interest. They are a population of ILCs that can induce the death of allogeneic and autologous cells undergoing malignant transformation and microbial infection. Early studies showing the importance of NK cells in the anti-tumor response were performed in mice. Several studies have shown a link in humans between low NK cell activity in peripheral blood and an increased risk of cancer. In addition, tumor infiltration by NK cells has been shown to be a favorable prognostic factor in non-small cell lung cancer (NSCLC), clear cell renal cell cancer and colorectal cancer. Immune Checkpoint Inhibitors (ICI) have been shown to be effective and to have manageable safety profiles for several cancer types. Their use has resulted in long-term survival, for more than a decade, in some patients with cancers for which significant therapeutic advances have been made, such as metastatic melanoma and NSCLC.  Along these lines, a therapeutic mAb blocking the three inhibitory KIR receptors for HLA-C was generated: Lirilumab (IPH2102, BMS-986015). Lirilumab is a fully human recombinant IgG4 that increases NK cell cytotoxicity against HLA-C-expressing tumor cells. The results of the effect of Lirilumab in clincal trials will be reviewed.

 Jeudi 15 juin à 15h00

Salle de conférences de l’IBGC

Sébastien Mongrand
Laboratoire de Biogenèse Membranaire – UMR 5200
CNRS – Université de Bordeaux – INRA Bordeaux Aquitaine
Invitation : Muriel Priault – IBGC UMR 5095
 “Structural Basis for Plant Plasma Membrane Protein Dynamics and Organization into Functional Nanodomains”

Plasma Membrane is the primary structure for adjusting to ever changing conditions. PM sub-compartmentalization in domains is thought to orchestrate signalling cascades. Yet, mechanisms governing membrane organization are mostly uncharacterized. The plant-specific proteins REMORINs are factors regulating hormonal crosstalk and host invasion. REMs are the best-characterized PM nanodomain markers targeted to the PM via an uncharacterized moiety called REMORIN C-terminal Anchor. By coupling biophysical methods, super-resolution microscopy and physiology, we decipher an original mechanism regulating the dynamic and organization of nanodomains. We showed that PM targeting is independent of the secretory pathway and mediated by PI4P and sterol. REM-CA is an unconventional lipid-binding motif that confers nanodomain organization. Analyses of REM-CA mutants by single particle tracking demonstrate that mobility and supramolecular organization are critical for immunity. This study provides a unique mechanistic insight into how the tight control of spatial segregation is critical in the definition of PM domain functionality

CONCEPTS IN CANCER SEMINAR SERIES

Invitation : Andreas Bikfalvi – Inserm U 1029

Gabrielle Bergers
VIB-KU Leuven Center for Cancer Biology
Department of Oncology, KU Leuven

Vendredi 9 juin à 11h00
Salle de conférences de l’IBGC

 “Crosstalk of the vascular and immune system in Cancer”

Sustained angiogenesis and immune suppression are hallmarks of cancer. There is increasing evidence that these two phenotypes are interconnected and facilitated by shared regulators not only during normal physiological processes, but also in cancer.

Tumors modify the homeostatic tissue repair program to their advantage by converting immune cells from an immunestimulating to an immunosuppressive and angiogenic phenotype and keeping blood vessels immunosuppressive. In line with the dual function of VEGF as a potent angiogenic and immune-suppressive factor, we had found that the efficacy of angiogenic inhibitors targeting the VEGF/VEGFR pathway hinged on their ability to induce an immune-stimulatory milieu in tumors by repolarizing innate immune cells to a Th1 phenotype, and that this capability dictated the degree of therapeutic response. Tumors in turn reacted to angiogenic blockade by producing factors that activated PI3K (g/d) signaling in intratumoral innate immune cells which converted them back into an immune suppressive and angiogenic state, and importantly disabled repolarization thereby rendering tumors resistant to anti-angiogenic therapy. More recently we discovered that the immunosuppressive relapse is also caused by upregulation of PD-L1, the ligand of the negative checkpoint regulator PD-1 found on T-cells, providing an adaptive immune-suppressive mechanism that limited the efficacy of anti-angiogenic agents. Using a combination of vascular and immune-modulating inhibitors, we were able to induce high endothelial venules (HEV) in tumors that are normally specialized to facilitate lymphocyte trafficking in lymphoid organs. HEV induction lead to the formation of tertiary lymphoid structures (TLS), centers of mixed immune infiltrates, that attacked tumor cells and elicited enhanced survival benefits.

CONCEPTS IN CANCER SEMINAR SERIES

Invitation : Andreas Bikfalvi – Inserm U 1029

Simone P. Niclou
Head of the NORLUX Neuro-Oncology Laboratory, Luxembourg Institute of Health, Luxembourg,

Adjunct professor at the Kristian Gerhard Jebsen Brain Tumour Research Center, Department of Biomedicine, University of Bergen, Bergen, Norway

“Resolving Genetic and Phenotypic Heterogeneity in Glioblastoma.”

Lundi 29 mai à 11h00
Salle de conférences de la Plateforme Génomique Fonctionnelle

The genetic and pathophysiological complexity of Glioblastomas represents a major obstacle for effective treatment. Extensive molecular profiling based on sequencing, transcriptomic, epigenetic and single cell analyses starts to provide a better delineation of tumour subtypes and underlying driver mutations. However such data also highlights the prominent heterogeneity between (inter) and within (intra) patient tumours. In our work, we aim to correlate genetic heterogeneity with differences in tumour phenotypes at the molecular, cellular and histopathological level. Data of GBM heterogeneity at the level of DNA ploidy and stem cell marker expression will be presented. Further I will discuss our established bank of patient-derived orthotopic xenografts (PDOX) that faithfully recapitulate human glioma and how they can be used to study treatment response in vivo. Our current understanding of inter- and intra-tumour heterogeneity will be presented and the challenges for effective therapies will be discussed.

Invitation : Katia Boniface – INSERM U1035 – Equipe Immunodermatologie ATIP-AVENIR

Mei Li
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)
CNRS-UMR7104 / INSERM U964 / Université de Strasbourg

“Keratinocytes in regulating skin immune responses: what do we learn from mouse models?”

Mardi 23 mai à 14h00
Salle de conférences de la Plateforme Génomique Fonctionnelle 

Skin immune responses are important for host defense against pathogenic microorganisms, but dysregulated immune responses in the skin also cause chronic inflammatory skin diseases including atopic dermatitis (AD).  In this seminar, I will take two examples from our studies over last years using mouse genetic tools and experimental models, to illustrate how epidermal keratinocytes (KCs) are recognized as initiator and regulator of skin and systemic inflammatory responses: 1) KC-derived cytokine thymic stromal lymphopoietin (TSLP) plays a key role in driving and coordinating the Type 2 Immunity in AD pathogenesis, as well as in triggering the progression from AD to asthma; 2) epidermal stratum corneum barrier dysfunction, resulted from gene mutations or environmental stimuli, leads to AD-like skin inflammation and allergen sensitization. We believe that insights obtained from mouse studies will be crucial for understanding the pathogenesis of skin inflammatory diseases, and will help to develop therapeutic/preventative strategies.


Mardi 16 mai à 11h00

IBGC

Mari Angels Juanes Ortiz
Brandeis University – Waltham, Massachussets, USA
 
Invitation : Isabelle Sagot – IBGC UMR 5095
 

“The tumor suppressor protein Adenomatous polyposis coli (APC) nucleates actin assembly to drive cell migration and proper focal adhesion turnover

A wide range of cellular processes including cell motility depend on tight coordination between the microtubule and actin cytoskeletons; however, the mechanisms underlying microtubule-actin crosstalk remain poorly understood. Here we show that the tumor suppressor protein Adenomatous polyposis coli (APC) nucleates actin assembly to promote directed cell migration. By changing only two residues in APC we generated a separation-of-function mutant, APC-m4, that abolishes actin nucleation activity without affecting microtubule interactions. Expression of full-length APC carrying the m4 mutation (APC-m4) rescued cellular defects in microtubule organization, microtubule dynamics, and mitochondrial distribution caused by depletion of endogenous APC, but failed to restore cell migration. While both wildtype APC and APC-m4 localized to focal adhesions, APC-m4 was defective in promoting actin assembly at focal adhesions and in responding to microtubule-induced focal adhesion turnover. These results provide the first direct evidence for APC-mediated actin assembly in vivo, and establish a new role for APC in microtubule-actin crosstalk at focal adhesions underlying directed cell migration.


Vendredi 5 mai à 14h00

IBGC

Bruce Goode
Brandeis University – Waltham, Massachussets, USA
 
Invitation : Isabelle Sagot – IBGC UMR 5095
 
 

“Microtubule-Actin Crosstalk: New Roles for Human Adenomatous Polyposis Coli (APC) in Cell Migration”

 

It has long been known that cell polarity and cell migration require tight functional coordination between the microtubule and actin cytoskeletons. However, the mechanisms underlying this microtubule-actin ‘crosstalk’ have remained elusive. In this talk I will highlight a 15 year path of discovery that started with defining the actin regulatory functions of formins in budding yeast, and eventually led us to uncover new functional roles for the human tumor suppressor protein Adenomatous polyposis coli (APC) protein in microtubule-actin crosstalk and directed cell migration. 


Jeudi 30 mars à 11h

Salle de Conférences de l’IBGC
Douglas Strathdee

Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, Scotland, UK.

Invitation : Deborah Tribouillard – IBGC UMR 5095

The phenotype of Taz null mutation in mouse closely resembles Barth Syndrome.”

An accurate mouse model of Barth Syndrome (BTHS) would greatly facilitate an understanding of the molecular bases of how mutation of the Tafazzin (Taz) gene causes the pleiotropic effects observed in the clinic. We have generated a mouse line carrying a conditional knockout mutation of the Taz gene. Analysis of RNA and protein confirmed the KO mice no longer express Taz. As observed in patients with Barth Syndrome, TazKO mice show decreases in levels of the mitochondrial phospholipid cardiolipin and increases in monolysocardiolipin levels, in heart, liver and skeletal muscle. The TazKO mice are around 30% smaller than their wild-type littermates at 6-8 weeks. KO males are born at less than 50% of the Mendelian ratio.  Preliminary and on-going phenotyping of Taz-KO mice using echocardiography and ECG indicate that Taz-KO mice exhibit cardiac left ventricular wall thinning, reduced cardiac systolic and diastolic function and prolongation of the QT interval. Assessment of mitochondrial morphology by electron microscopy shows substantial alterations in the TazKO mice, particularly in the heart.  Expression profiling of heart tissue and metabolomic analyses of heart, plasma and urine confirmed significant alteration of mitochondrial function in the TazKO mice. Taken together these results suggest these mice represent a good model of the clinical consequences of Barth Syndrome, which will be useful for understanding the processes underlying the disease and for testing the efficiency of possible therapies, to reverse the changes observed in the TazKO mice.


Mardi 14 mars à 11h
Salle de Conférences de l’IBGC

Beat Imhof
Department of Pathology and Immunology, University of Geneva

Invitation : Alain Taieb – Inserm U 1035

“New Molecular Targets for Angiogenesis driven diseases.”

Angiogenesis is a process that plays a key role in tumor development, wound healing and chronic inflammation. We and others found that recruitment of a subpopulation of human angiogenic monocytes and the production of the matricellular molecule Olfml-3 are two critical cues. We studied extravasation of these monocytes by using human tumor xenograft models and live-imaging of trans endothelial migration of proangiogenic monocytes composed of CD14dimCD16+ patrolling and CD14+CD16+ intermediate cells. We found that the inflammatory cytokine IFNg-increased expression of CX3CL1 chemokine on vascular endothelium and mediates retention of pro-angiogenic monocytes in the vascular lumen. Expression of the angiogenic factor VEGF and the inflammatory cytokine TNFa by tumor or inflamed cells specified a molecular expression program in the endothelium that caused CX3CL1 repression and allowed extravasation of these monocytes. The de novo recruited proangiogenic monocytes boosted tumor angiogenesis by secreting MMP-9, leading to release of matrix bound VEGF, and by this way amplifying the entry of more proangiogenic monocytes into tumors. Uncovering the luminal retention role of CX3CL1 and this cancer-related recruitment process sets the stage for future approaches in tumor and chronic inflammation therapies. The second mechanism that will be described is driven by matricellular molecules that bridge the cell surface to the extracellular matrix and forms a microenvironment for angiogenic endothelium. Our laboratory recently described Olfactomedin-like 3 (Olfml3), a novel matricellular molecule with the ability to regulate vascular remodeling under normal and pathological conditions. Olfml3 is expressed at high levels during development in the presumptive vasculogenic regions of the embryo. Yet, Olfml3 knockout mice are viable but exhibit mild vascular morphogenetic defects. Expression of Olfml3 in adult animals is largely limited to tissue undergoing remodeling including placenta and tumors. Tumor-derived Olfml3 is produced by both tumor endothelial cells and accompanying pericytes, and deposited in the perivascular compartment. Olfml3 alone or through binding to bone morphogenetic protein 4 (BMP4), a potent pro-angiogenic growth factor, enhances the canonical SMAD1/5/8 signaling pathway required for BMP4-induced angiogenesis. Blockade of Olfml3 by anti-Olfml3 antibodies is highly effective in reducing tumor vascularization, pericyte coverage, and tumor growth. These findings indicate that Olfml3 blockade provides a novel strategy to control tumor growth by targeting two distinct cell types within the tumor microenvironment using a single matricellular molecule. Given the potential side effects and resistance linked to current anti-angiogenic therapies, a better understanding of novel angiogenic signaling circuits can accelerate the development of alternative and more selective strategies. Blocking Olfml3 and pro-angiogenic monocytes are two examples.


Jeudi 9 mars à 11h
Salle de Conférences de la Plateforme Génomique Fonctionnelle


CONCEPTS IN CANCER SEMINAR SERIES
Timothy M. Thomson

Laboratory of Cell Signaling and Cancer – Institute for Molecular Biology
Science Research Council (CSIC) Barcelona Science Park

Invitation : Andreas Bikfalvi – Inserm U 1029

“Metabolic Reprogramming in Cancer Stem Cells and Acquired Drug Resistance”

Metabolic reprogramming underlies the fitness and growth advantage of cancer cells. Tumors contain heterogeneous populations of neoplastic cells that are reflected in heterogeneous metabolic networks. I will present our findings of differential metabolic networks in cells populations displaying CSC vs. non-CSC phenotypes using a clearcut dual-cell model. I will also present evidences that adaptive metabolic responses of cancer cells to the cell-cycle inhibitor palbociclib significantly overlap key metabolic profiles and regulatory networks of CSCs. Such metabolic adaptations represent actionable vulnerabilities that can be targeted in novel approaches for neoplastic subpopulation-directed therapies and to overcome acquired drug resistance.


Vendredi 24 février à 11h
Salle de Conférences de la Plateforme Génomique Fonctionnelle

Rolando Herrero
Jin Young Park – Prevention and Implementation Group
International Agency for Research on Cancer/WHO – Lyon, France

Invité par Francis Mégraud – Inserm U 1053

“The IARC Research Program on H pylori and gastric cancer”

Gastric cancer is a leading cause of cancer death worldwide,  with almost 1 million cases a year and 750,000 deaths.  Regional variations  up to 30-fold  are observed between high and low risk areas without  a clear explanation. Chronic H pylori infection is an established cause of approximately 90% of gastric cancers and the natural history and precursor lesions have been established (Correa cascade).   However, the interaction between bacterial, host and environmental cofactors leading to gastric cancer remains to be fully elucidated.  H pylori treatment is feasible with combination antibiotics and proton pump inhibitors,  and has been associated in clinical trials with an approximately 30% reduction in gastric cancer risk in studies conducted mainly in China. However,  very few public health programs to screen and treat the bacterium have been established,  partly because of the high prevalence of infection and partly because of the limited data on potential adverse consequences on the microbiome,  antibiotic resistance and esophageal diseases, among others.  The IARC research program on H pylori includes the ENIGMA studies,  consisting of prevalence surveys of H pylori infection and gastric cancer precursors in high- and low-risk areas of the disease,  to explore the reasons for the large regional variations observed.  Age- and sex-stratified population samples are recruited for interview and collection of multiple biologic specimen for assessment of bacterial,  host and environmental factors underlying the regional variation.  The HELPER study is a multicentric randomized double blind clinical trial in Korea that will recruit 11,000 subjects attending the national screening program.  Participants testing H pylori positive in gastric tissue are randomized to quadruple eradication therapy or placebo and followed endoscopically for up to 10 years to assess incidence of gastric cancer and adverse events.  GISTAR is a study in Latvia and other possible high incidence areas in Europe where subjects are randomised to screening with an H pylori test and pepsinogen or no screening.  In the screening arm,  H pylori positive subjects are eradicated and those with pepsinogen alterations are followed with endoscopic evaluation according to European guidelines.  A total of 30,000 subject recruitment is planned with passive follow-up for 15 years.


Mardi 21 février à 11h
Salle de Conférences de la Plateforme Génomique Fonctionnelle

Clarisse Berlioz Torrent

Laboratoire « Interaction Hôte-Virus» – Institut Cochin

Inserm U1016-CNRS UMR8104-Université Paris Descartes

Invitation : Vincent Parissi – MFP CNRS 5234

“Voie endosomale et Voie non-canonique d’autophagie: Comment le virus VIH-1 utilise ces machineries cellulaires pour contrer le facteur de restriction viral BST2/Tetherin.”

La dissémination du Virus de l’Immunodéficience Humaine de type 1 (VIH-1) est un déterminant essentiel de la progression de la maladie vers le stade SIDA chez le sujet infecté. Pour contrer la propagation des virus, l’hôte a développé un arsenal de défenses immunes, dont des défenses cellulaires innées mettant en jeu des interactions entre protéines virales et protéines cellulaires. Parmi les composants de cette défense innée dirigée contre le VIH-1, on trouve les facteurs dit de « restriction », dont la protéine cellulaire BST2 pour « Bone marrow stromal antigen 2 », aussi nommée Tetherin. Ce facteur retient physiquement les nouveaux virus formés à la surface de la cellule productrice, réduisant de facto leur bourgeonnement et donc la production et la dissémination virale. Le groupe de Clarisse Berlioz-Torrent à l’Institut Cochin (U1016 Inserm, UMR 8104 CNRS, Université Paris Descartes Sorbonne Paris Cité) étudie comment le virus contre cette restriction virale. En effet, face à cette restriction, le virus a développé différentes stratégies pour diminuer le niveau d’expression de la protéine BST2/Tetherin présente au site de bourgeonnement viral et restaurer ainsi une production virale efficace. La protéine Vpu du VIH-1 est l’un des acteurs viraux capable de contrer cette barrière innée. En étudiant de plus près cette restriction virale, l’équipe de Clarisse Berlioz-Torrent a découvert que le virus VIH-1 via Vpu utilise la voie endosomale et une forme d’autophagie non canonique pour contrecarrer efficacement la restriction virale induite par BST2. Ce travail a été réalisé avec le soutien financier de l’ANRS et de SIDACTION.

 

En savoir plus:

LC3C contributes to Vpu-mediated antagonism of BST2/Tetherin restriction on HIV-1 release through a non-canonical autophagy pathway. Ursula Madjo§, Olivier Leymarie§, Stéphane Frémont, Aurélia Kuster, Mélanie Nehlich, Sarah Gallois-Montbrun, Katy Janvier and Clarisse Berlioz-Torrent. § Co-first authors. Cell Reports 2016 17, 1-13.

Rab7A is required for efficient production of infectious HIV-1. Caillet M, Janvier K, Pelchen-Matthews A, Delcroix-Genête D, Camus G, Marsh M, Berlioz-Torrent C. PLoS Pathog. 2011 Nov;7(11):e1002347.

Janvier K.*, Pelchen–Matthews A., Renaud J.B., Caillet M., Marsh M., Berlioz–Torrent C*. The ESCRT–0 component HRS is required for HIV–1 Vpu–mediated BST2/Tetherin down–regulation. PloS Pathogens. 2011 Feb 3;7(2):e1001265.


Jeudi 16 février à 11h
Salle de Conférences de la Plateforme Génomique Fonctionnelle 

CONCEPTS IN CANCER SEMINAR SERIES

Jean-Philippe Girard

Institut de Pharmacologie et de Biologie Structurale, CNRS-Université de Toulouse

Invitation : Andreas Bikfalvi – Inserm U 1029


Les vaisseaux HEV: des vaisseaux sanguins spécialisés qui combattent le cancer”

Des stratégies thérapeutiques visant à inhiber la formation des vaisseaux sanguins (angiogenèse) ont été développées, car les vaisseaux sanguins contribuent à la croissance des tumeurs en fournissant notamment l’oxygène et les éléments nutritifs dont les cellules cancéreuses ont besoin pour survivre et se multiplier. Cependant, tous les vaisseaux sanguins ne sont pas équivalents et nous venons de découvrir que certains vaisseaux très spécifiques, les vaisseaux HEV, contribuent à lutter contre les tumeurs solides plutôt qu’à les favoriser (Martinet, … and Girard, Cancer Res 2011). Ces vaisseaux HEV (pour High Endothelial Veinules), sont généralement présents dans les ganglions lymphatiques où ils constituent la porte d’entrée pour les lymphocytes arrivant par le sang (Girard et al, Nat Rev Immunol 2012). Les vaisseaux HEV sont souvent présents dans le stroma des tumeurs solides humaines et ils semblent favoriser l’accès aux tumeurs des lymphocytes T cytotoxiques (« lymphocytes tueurs »), capables de détruire les cellules cancéreuses. Dans le cancer du sein, nous avons montré que plus le nombre de vaisseaux HEV est important, plus le risque de métastases diminue et plus l’espérance de vie augmente. A l’inverse, dans les cancers hématologiques (lymphomes et leucémies telles que la leucémie lymphoïde chronique), les vaisseaux HEV, en permettant l’entrée des cellules cancéreuses dans les ganglions lymphatiques, pourraient favoriser la résistance aux traitements chimio-thérapeutiques (Lafouresse,… and Girard, Blood 2015). Les mécanismes moléculaires et cellulaires impliqués dans la régulation des vaisseaux HEV sont encore peu connus, bien que nos données suggèrent un rôle clé des cellules dendritiques CD11c+ dans ce processus (Moussion and Girard, Nature 2011).

Le rôle des vaisseaux HEV dans le cancer (tumeurs solides et cancers hématologiques) sera présenté au cours du séminaire. Nos résultats récents sur la caractérisation moléculaire des vaisseaux HEV par des approches « single cell RNA-Seq » et l’influence des vaisseaux HEV sur la réponse aux agents anti-cancéreux seront discutés.

Publications :
1) Moussion C and Girard JP. Dendritic cells control lymphocyte entry into lymph nodes via high endothelial venules. Nature, 2011, 479:542-546
2) Martinet L*, Garrido I*,  Filleron T, Le Guellec S,  Bellard E, Fournie JJ, Rochaix P and Girard JP. Human solid tumors contain high endothelial venules (HEVs): association with T and B lymphocyte infiltration and favorable prognosis in breast cancer. Cancer Res, 2011, 71:5678-5687
3) Girard JP*, Moussion C and Forster R. HEVs, lymphatics and homeostatic immune cell trafficking in lymph nodes. Nature Rev Immunol, 2012, 12:762-773 (*Corresponding author)
4) Lafouresse F, Bellard E, Laurent C, Moussion C, Fournié JJ, Ysebaert L and Girard JP. L-selectin controls trafficking of chronic lymphocytic leukemia cells in lymph node high endothelial venules in vivo. Blood, 2015, 126:1336-1345 (This article has been selected by the Editors for the cover of the journal and a research highlight in “Inside Blood” 2015, 126:1267-1268)


Mardi 14 février à 11h
Salle de Conférences de l’IBGC

Corinne Augé-Gouillou
Université de Tours – UMR 990

Invitation : Vincent Parissi – MFP CNRS 5234

Transposons et cancer : Comment un élément génétique mobile de classe II contrôle la stabilité de notre génome…

Nous étudions l’implication du réseau lié à Hsmar1 (un élément génétique mobile de classe II)  dans la biogenèse d’une tumeur très agressive, le  glioblastome multiforme (GBM). Ce réseau est issu de la propagation d’Hsmar1, un élément génétique mobile constitutif du génome humain. Il dépend -d’une part- de la présence de copies dispersées (complètes ou non) d’Hsmar1 dans les introns des gènes codant pour des protéines, ou dans des gènes codant pour des ARN régulateurs. Ce réseau dépend également de la capacité de SETMAR, une protéine issue évolutivement d’Hsmar1, à se fixer aux milliers de séquences ITR (également dérivées d’Hsmar1) présentes dans le génome humain. Nous avons montré au laboratoire que SETMAR existait sous deux formes différentes en fonction du type de cellule tumorale : la forme « classique » est majoritaire dans les cellules différenciées de la tumeur, alors qu’un variant hyper-stable de plus petite taille est majoritaire dans les cellules souches de la tumeur. Notre hypothèse est que chaque forme régule un réseau de gènes différent via le réseau Hsmar1. L’identification des réseaux et gènes associés ouvrira des pistes dans la définition de nouvelles cibles thérapeutiques.


Vendredi 10 février à 14h

Bibliothèque du service de néphrologie – CHU Pellegrin
Oriol Manuel
Service des Maladies Infectieuses – Lausane 

“Immune Monitoring for CMV : Challenges and new Developments”

Invitation : Pierre Merville

Cytomegalovirus (CMV) infection is one of the main infectious complications occurring after organ transplantation. Novel strategies are needed to further reduce the burden of cytomegalovirus (CMV) disease in solid-organ transplant (SOT) recipients. Measurement of the specific cell-mediated immunity against CMV can identify the actual risk for the development of CMV disease in a given patient and, therefore, is an attractive strategy for individualizing the management of CMV after transplantation. In this lecture, I will summarize the existent literature and own experience on immune monitoring for CMV. A growing number of observational studies have been published over recent years, although there is a lack of data coming from interventional trials. In high-risk patients, measurement of CMV-specific T-cell responses appropriately stratifies the risk of CMV disease after discontinuation of antiviral prophylaxis. Immune monitoring may also help to identify patients followed by the preemptive approach at low risk for progression to CMV disease. Pretransplant assessment of cell-mediated immunity in seropositive patients may predict the development of posttransplant CMV infection. Overall, these studies indicate that the use of cell-mediated immunity assays has the potential to improve the management of CMV disease in SOT recipients.


Jeudi 9 février à 11h
Salle de Conférences de l’IBGC

Françoise DegoulJacques Rouanet – Hussein Akil
Université d’Auvergne – UMR 990

Invitation : Muriel Cario-André – Inserm U1035

Radiothérapie interne du mélanome métastasé

L’UMR 1240 INSERM/Université Clermont Auvergne propose une approche focalisée principalement, mais de façon non exclusive, vers le diagnostic et le traitement de la maladie cancéreuse. Notre stratégie repose sur le développement de vecteurs moléculaires capables de cibler un tissu ou un mécanisme biochimique particulier. Le radiomarquage de ces vecteurs ouvre des champs d’application prometteurs pour la radiothérapie interne (RTI) et/ou l’imagerie scintigraphique de nombreuses pathologies parmi lesquelles le mélanome. Les molécules traceurs de mélanines sélectionnées pour l´imagerie et la thérapie sont très sélectives des tissus pigmentés (Cachin et al, 2014 ; Viallard et al, 2014 ; Rbah-Vidal et al, 2016). Cette propriété implique une sélection des patients à inclure lors du transfert clinique, la phase I consistera d´ailleurs en une étude d´escalade de dose d´[131I]ICF01012. Nous avons montré que des petites molécules d´ADN (CoDbait) désorganisant les systèmes de réparation potentialisent l´effet de la RTI (Viallard et al, 2016). Des études sur des sphéroïdes pour analyser la réponse à la RTI en fonction de la pigmentation et du statut BRAF/PTEN seront également présentées.

Cachin F, J Nucl Med. 2014 Jan;55(1):15-22. doi: 10.2967/jnumed.113.123554.
Viallard C Eur J Dermatol. 2015 Jan-Feb;25(1):29-35. doi: 10.1684/ejd.2014.2481.
Viallard C. Oncotarget. 2016 Mar 15;7(11):12927-36. doi: 10.18632/oncotarget.7340
Rbah-Vidal L, Neoplasia. 2016 Dec 14;19(1):17-27. doi: 10.1016/j.neo.2016.11.001


Mercredi 25 janvier à 11h
Salle de Conférences IBGC

Prof Guillermo Perez Perez
Departments of Medicine and Microbiology, New York University Langone Medical Center
Université de New York – New York, USA

Invité par Francis Mégraud – Inserm U 1053

“Revisiting the epidemiology of Helicobacter pylori : mode of transmission”

Epidemiology of H. pylori has been clearly defined since the isolation of this bacterium in 1982. It is now clear that H. pylori infection is acquired early in life, most likely in the family setting. The H. pylori status of the mother is the major risk factor for the child to be colonized. However, transmission of H. pylori among humans has not been clearly identified despite more than 30 years of research dedicated to this issue. Several H. pylori transmission routes have been proposed including direct (oral-oral, gastro-oral and fecal-oral) as well as indirect routes (food, animals and drinking water). The latter are controversial and all of them are still poorly understood.

It is remarkable that only a few studies have described the isolation of H. pylori from stool samples, and this under special conditions. Furthermore, presence of H. pylori in the stool has been documented using PCR or nested PCR but the results are also controversial.

An indication of possible fecal-oral transmission in H. pylori is the detection of H. pylori stool antigens, a diagnostic that has been found very useful for detection of active H. pylori infection. According to this, one may expect a high proportion of live H. pylori in the gut microbiota. However, earlier reports indicated the lack of H. pylori sequences in feces of patients with confirmed gastric H. pylori infection. Therefore a clear confirmation of the presence of H. pylori in feces is needed.

A second generation sequencing has been used to determine the presence of bacteria without culturing and determine the microbiota composition of different ecological niches including the human body. Different studies have been performed using techniques to determine the presence of H. pylori in feces. The studies included the use of animal models such as mice and monkeys, as well as human subjects, including symptomatic adults and children in addition of asymptomatic young adults. The highlights of those studies will be presented with an emphasis on the most consistent observation which is the lack of Helicobacter sequences in feces. We will discuss if the fecal-oral route is a valid mechanism in the transmission of H. pylori in human populations.


Mercredi 18 janvier à 14h30
Salle de Conférences IBGC

Christian Stockmann
Institut National de la Santé et de la Recherche Médicale (INSERM), Unit 970,
Paris Cardiovascular Research Center, Paris, France

Invitation : Andreas Bikfalvi – Inserm U1029

“The hypoxic response in Natural Killer cells: Linking immune surveillance and tumor angiogenesis”

Innate immune cells, notably the myeloid lineage, are critical for shaping immune responses within the tumor microenvironment by controlling angiogenesis and tumor oxygenation. Cellular adaptation to low oxygen (hypoxia) depends on Hypoxia-inducible transcription factors (HIFs) which also play a pivotal role in inflammatory responses. NK cells unifying characteristics of innate and adaptive immunity, are cytotoxic innate lymphoid cells with a unique ability to instantly recognize and kill “aberrant” cancer cells while sparing “normal” cells. Owing to these tumoricidal features, NK cells are able to restrict primary tumor growth and limit metastatic spread. We observe that Natural Killer (NK) cells preferentially infiltrate into hypoxic zones of solid primary tumors and by genetic targeting of HIFs in NK cells, we define a crucial role of HIF-1α in NK cell function and cancer immune surveillance. HIF-1α-deficiency in NK cells impairs cytotoxicity and killing of tumor cells in vitro.

Furthermore, we define the hypoxic response in NK cells as a critical mediator of tumor angiogenesis. Paradoxically, HIF-1α-deficiency in NK cells results in decreased expression of various angiostatic factors within the tumor microenvironment, resulting in unproductive tumor angiogenesis, characterized by immature, non-functional vessel and severe tumor hypoxia. This suggests that the hypoxic response in NK cells slows down overall tumor angiogenesis in order to allow for vessel formation in a more coordinated fashion.

In summary, we define HIF-1α as a critical mediator of NK cell effector function and cancer immune surveillance. Secondly, we show that HIF-1α in NK cells acts as a negative regulator of tumor angiogenesis that ensures the fine-tuning of the angiogenic response.


Mardi 10 janvier à 14h
Salle de conférences de la Plateforme Génomique Fonctionnelle,

site de Carreire zone sud, université de Bordeaux

Audrey Dussutour
Centre de Recherches sur la Cognition Animale
UMR 5169 CNRS, Université Toulouse
Invitation : Thomas Pradeu – CNRS 5164

“Learning in brainless organisms : evidence from slime molds”

Learning, defined as a change in behaviour evoked by experience, has hitherto been investigated almost exclusively in multicellular neural organisms. Evidence for learning in non-neural multicellular organisms is scant and only a few unequivocal reports of learning have been described in single celled organisms. In this seminar, in a first part, I will demonstrate habituation, an unmistakable form of learning, in the non-neural organism Physarum polycephalum. In a second part, I will show that learned information can be transferred from one cell to another via cell fusion. Our results point to the diversity of organisms lacking neurons, which likely display a hitherto unrecognized capacity for learning, and suggest that slime moulds may be an ideal model system in which to investigate fundamental mechanisms underlying learning processes.

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