Molecular Basis of Inflammation

  • Chronic Inflammation is a poor prognosis factor for cancer patients as it promotes every step of tumorigenesis, from initiation to metastasis. While it has been long known that cancer-promoting inflammation can be linked to environmental conditions such as exposition to asbestos, intrinsic factors have also been incriminated as directly affecting the inflammatory response. Such endogenous triggers for chronic inflammation include immune-stimulatory nucleic acids that accumulate in the cytosol of cancer cells and are recognized by the innate immune system. Collectively, recent evidences point towards an involvement of the STING-cGAS pathway in recognizing cytosolic DNA species and stimulating production of inflammatory mediators.

    The “Molecular Basis of Cancer-Related Inflammation” lab investigates the molecular mechanisms that underlie the onset of chronic inflammation. Our primary models of study are familial cancer susceptibility syndromes, pancreatic adenocarcinoma, and infections with retroviruses. We address the nature, the biogenesis and regulation of immune-stimulatory cytosolic nucleic acids. We investigate alternative nucleic acid sensing routes and regulators of the cGAS-STING recognition pathway.

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    To date, our research is funded by:

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    Members

    Nadine Laguette
    Laguette Nadine
    Jessica Guerra
    Guerra Jessica
    Katarzyna Polak
    Polak Katarzyna
    Ana-Luiza Valadao
    Valadao Ana-Luiza
    Isabelle Vila
    Vila Isabelle
    Johanna Marines
    Marines Johanna
    Clara Taffoni
    Taffoni Clara

    Publications

    V1b vasopressin receptor trafficking and signaling: Role of arrestins, G proteins and Src kinase.

    Perkovska S, Méjean C, Ayoub MA, Li J, Hemery F, Corbani M, Laguette N, Ventura MA, Orcel H, Durroux T, Mouillac B, Mendre C

    2017 - Traffic, 19(1):58-82

    Request for full article29044966

    Upregulated LINE-1 Activity in the Fanconi Anemia Cancer Susceptibility Syndrome Leads to Spontaneous Pro-inflammatory Cytokine Production

    Bregnard, C, Guerra, J, Dejardin, S, Passalacqua, F, Benkirane, M, Laguette, N

    2016 - EBioMedicine, 8, 184-194

    Request for full article27428429

    Shaping of the host cell by viral accessory proteins

    Laguette N, Benkirane M.

    2015 - Front Microbiol., 6, 142

    Request for full article25755653

    Premature Activation of the SLX4 Complex by Vpr Promotes G2/M Arrest and Escape from Innate Immune Sensing

    Laguette,N., Bregnard, C., Hue, P., Basbous, J., Yatim, A., Larroque, M., Kirchhoff, F., Constantinou, A., Sobhian, B., Benkirane, M.

    2014 - CELL, 156, 1-2, 134-145

    Request for full article24412650
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    Publications of the team

  • Recognition and regulation of cytosolic DNA:RNA hybrids

    We have recently shown that increased endogenous retroelement-associated reverse transcriptase (RT) activity generates immunogenic nucleic acids. These nucleic acids are recognized through the cGAS-STING pathway to sustain chronic inflammation in the Fanconi Anemia cancer susceptibility syndrome. We now focus on the recognition and clearance of endogenous RT-generated immunogenic nucleic acids. We use models of cancer susceptibility syndromes together with retroviral invefctions to investigate the fate of RT activity generated immune-stimulatory nucleic acids.

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    Regulation of chemoresistance by the innate immune system

    There is growing evidence that presence of immunogenic cytosolic nucleic acids (NAs) can initiate cancer-related inflammation through stimulation of STING-cGAS sensing. However, the role of cytosolic NAs and of innate immune signaling in promoting chemo-resistance is still unknown. We use pancreatic adenocarcinoma (PDAC) as a model to investigate the role played by the innate immune system in regulating chemoresistance. Specifically, we investigate the role of endogenous NAs in the onset of chronic inflammation in PDAC, using human and murine cell lines as well in vivo approaches in murine models.

    Alternative DNA sensing pathways

    Genotoxic stress response is a complex network of molecular interactions and post-translational modifications triggered by genetic instability and DNA replication stress undergone by cancer cells. Genotoxic stress response proteins are direct regulators of the innate immune response through (i) their ability to recognize non-canonical nucleic acid structures, including self-DNA present in the cytosol and (ii) the regulation of DNA repair. Mounting evidence suggest the existence of DNA sensing routes that are distinct from the canonical cGAS–STING pathway and that act in a tissue and cell type specific manner. We use a unique set of in vivo and in vitro tools to interrogate the regulation of DNA recognition and its impact on immune responses.

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    Obesity, inflammation and cancer risk

    Obesity and diabetes are associated with many types of cancers and several studies have reported a deleterious effect of high fat diets on tumorigenesis. Obesity increases systemic and adipose tissue inflammation in humans and mice, leading to a state of low-grade inflammation resulting in a higher production of cytokines and chemokines. We explore the role of adipose-tissue associated inflammation in tumorigenesis in vivo in order to uncover the contribution of intra- and inter-organ communication to the initiation, progression and chemo-resistance.

  • Education/Academic Positions

    2015 - Group Leader – Molecular basis of Cancer-Related Inflammation Lab., IGH (UPR 1142), Montpellier, France
    2014 - HDR at University of Montpellier I, France
    2012-2014 CR2 CNRS – Molecular Virology Lab., IGH (UPR 1142), Montpellier, France
    2009-2012 - Postdoc – Molecular Virology Lab, IGH (UPR 1142), Montpellier, France
    2005–2008 - PhD in Cell Biology – Cochin Institute, University Paris V, France
    2004–2005 - Master2 in Cell Biology – University of Paris V, France
    2003–2004 - Master1 in Cell Biology and Physiology – University of Paris XI, France
    2000–2003 - BSc in Molecular Biology and Genetics – RHUL, London, UK

    Awards

    2015 - “Georges Frêche – Université Sud de France” Award
    2015 - ERC Starting Grant
    2014 - Sanofi-Pasteur Institute Young Investigator Award
    2013 - CNRS “Prime d’Excellence Scientifique”
    2012 - SIDACTION “Prix jeune chercheur 2012”
    2012 - Cold Spring Harbor RETROVIRUSES Meeting “Andy Kaplan Prize”
    2012 - French Academy of Science : “Les grandes avancées françaises 2011-2012 en biologie présentées par leurs auteurs”