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photo equipe paradis couvineau 2024

From inflammation to cancer in digestive diseases (INDiD)

Team Paradis / Couvineau

Department Hepato-Gastroenterology Department







Chronic digestive diseases, especially in the context of metabolic syndrome (MS), represent a main public health issue with increasing prevalence of inflammatory-related disorders involving liver and pancreas, that favor the development of cancers. Obesity and MS constitute common and emerging risk factors for liver and pancreatic cancers. In that context, we focus on the physiopathology of the inflammation ‐-> cancer sequence in the digestive system to explore the cellular and molecular mechanisms involved in preneoplasia to cancer that would increase our knowledge and provide new therapeutic strategies.

Our research is organized along 3 axes:

Liver Axis

  1. Decipher the role of endothelial cells in the development and progression of hepatocellular carcinoma related to metabolic syndrome (HCC-MS): We have demonstrated the prooncogenic effect of endothelial Fatty acid binding protein 4, and are exploring the role of endothelial autophagy in HCC development (Laouirem S, Oncogene 2019). We are actually exploring the process of endothelial to mesenchymal transition in that setting (Fondation ARC 2024).
  2. Identify new tissue biomarkers in liver cancerogenesis through innovative technologies: We established a 6 gene signature predictive of microvascular invasion in HCC by a nanostring approach (Beaufrère, J Hep 2022). Using mass spectrometry imaging, we described the molecular landscape of cholangiocarcinomas and deciphered intratumor heterogeneity in the wide spectrum of primary liver carcinomas (Le Faouder, Proteomics Clin Appl 2019; Gigante, Cancers 2023). We use deeplearning approaches and AI to improve morphological diagnosis of liver cancers (Beaufrère, JHEP Rep 2024).
  3. Explore tissue heterogeneity via Precision-Cut-Tissue Slices and 3D co-cultures with organoids: These models better reflect cell heterogeneity and their micro-environment, and are currently used to evaluate drug sensitivity in different clinical contexts (Metabolic diseases and tumors) (Hammoutène, JHEP Rep 2023). We are building a Tissue slicer platform (SLAICER) to design chemograms able to identify the cancers responsive or resistant to antitumoral therapies (Ligue Nationale Contre le Cancer 2024)

Pancreas Axis

  1. Identify factors and molecular mechanisms of pancreatic inflammation/regeneration and development of precancerous lesions: We found that lack of the transcription factor Hnf1b leads to pancreatitis and facilitates tumorigenesis with pancreatic intraepithelial neoplasia (PanIN) development (Quilichini, Cell Mol Gastroenterol Hepatol 2019). We highlighted the etiology and pathophysiology of the MODY5/HNF1B pancreatic phenotype in a mouse model of the human disease (Quilichini, J Pathol 2021). We investigate the role of Hnf1b in intraductal papillary mucinous neoplasm IPMN initiation (Ligue Contre le Cancer 2022, Fondation ARC Fellowship). We also study factors involved in ADM and PanIN development (Marstrand-Daucé, Int J Mol Sci. 2023).
  2. The role of MS and obesity in the development of precancerous lesions: We demonstrated that fatty pancreas was associated with higher BMI, fibrosis and PanIN, and the increased in preneoplastic lesions and fat infiltration in rat model (high-fat diet followed by bariatric surgery) by quantitative elasto-MRI (Rebours, Sci Rep 2018). We investigate the mechanisms involved and develop MRI sequences to improve detection of early pancreatic lesions in patients (PAIR Program 2018).
  3. Heterogeneity and plasticity of pancreatic neoplasms and their precursor lesions: We studied the intertumor heterogeneity of tumor cells (Puleo, Gastroenterology 2018; Hilmi, Eur J Cancer 202; Zao, Clin Cancer Res 2021), stroma (Neuzillet, J Pathol 2019, 2022) and their clinical impact using AI models (Saillard, Nat Commun 2023). To stratify patients, we developed several predictive biomarkers to gemcitabine sensitivity, a central drug in PDAC, by different approaches (Raffenne, Cancers 2019; Piquemal, Cancers 2020; Bachet, Clin Cancer Res 2020; Nicolle, Ann Oncol 2021; Trans Oncol 2022, J Clin Oncol 2023). Our goals are now (i) to understand the biological queues behind the massive morphological heterogeneity of pancreatic adenocarcinomas and neuroendocrine tumors through spatial multiomics profiling (MALDI imaging-spatial transcriptomics coupled with AI) (INCa PRTK 2020, PL-BIO 2023, MIC 2022, NRFT 2022), (ii) to develop innovative AI or transcriptomic-based biomarkers to predict the risk of evolution of the most frequent type of pancreatic preneoplastic lesions, IPMN (Fondation ARC 2023, Ligue Contre le Cancer 2019, RHU OPERANDI 2022).


OXA/OX1R system in inflammation and digestive cancer axis:

  1. Anti-inflammatory properties of the OxA/OX1R system: Orexin receptors (OX1R and OX2R) which interact with orexins (OxA and OxB), are aberrantly expressed in digestive inflammation and cancer but not in healthy tissues (Couvineau et al., 2018,2019,2020,2021,2022). We demonstrated that OX1R is expressed in inflammatory bowel disease (IBD), pancreatitis, multiple sclerosis and MS, where OxA induced an anti-inflammatory effect (Messal N, Biochim Biophys Acta Mol Basis Dis. 2018). OxA strongly reduced multiple sclerosis symptoms (Becquet, J Neuroinflammation 2019) and reduced the fat mass in mice (Blais et al., PLOS One 2017).
  2. Anti-tumoral properties of the OxA/OX1R system: OX1R is expressed in digestive cancers including pancreas, liver, colon and lung cancers. We identified the antitumoral role of OxA in digestive cancers in which OxA induced SHP2-dependent apoptosis and led to an anti-tumoral effect in preclinical models (Dayot S, Oncotarget 2018). The OxA/OX1R system displayed anti-tumoral actions in chemotherapy-resistant PDAC (Voisin T, Front Oncol 2022). Antitumor antagonists were shown to be able to trigger SHP2-dependent apoptosis involving the Gq protein (Gratio, Cytometry 2023). We developed a synthetic antibody which mimicked the anti-tumoral role of orexin in PDAC and other cancers (European Sanofi iAward 2020-2021, Patent).

Landmark publications

  • Publication date : 28 November 2023 More

    Imaging flow cytometry of tumoroids: A new method for studying GPCR expression
    Cytometry A.

    Authors : Gratio Valérie Dayot Stephanie Benadda Samira Nicole Pascal Saveanu Loredana Voisin Thierry Couvineau Alain

  • Publication date : 30 October 2023 More

    Differential diagnosis of small hepatocellular nodules in cirrhosis: surrogate histological criteria of TERT promoter mutations

    Authors : Beaufrère Aurélie Paisley Sarah Ibrahima Ba Laouirem Samira Priori Victoria Cazier Hélène Loëtitia Favre Cauchy François Lesurtel Mickaël Julien Calderaro Kannengiesser Caroline Paradis Valérie

  • Publication date : 01 October 2023 More

    Pathological overview of steatohepatitic hepatocellular carcinoma in a surgical series

    Authors : Loïc Trapani Beaufrère Aurélie Christian Hobeika Tatiana Codjia ALBUQUERQUE Miguel Mohamed Bouattour Lesurtel Mickaël Cauchy François Paradis Valérie

  • Publication date : 12 July 2023 More

    A new NRF2 activator for the treatment of human metabolic dysfunction-associated fatty liver disease
    JHEP Rep.

    Authors : Hammoutene Adel Laouirem Samira ALBUQUERQUE Miguel Nathalie Colnot Brzustowski Angelique Valla Dominique Nicolas Provost Philippe Delerive Paradis Valérie QUID-NASH Research Group

  • Publication date : 12 June 2023 More

    Editorial: A year in review: discussions in molecular and structural endocrinology
    Front Endocrinol (Lausanne).

    Authors : Couvineau Alain Ernestina Marianna De Francesco

  • Publication date : 09 June 2023 More

    Acinar-to-Ductal Metaplasia (ADM): On the Road to Pancreatic Intraepithelial Neoplasia (PanIN) and Pancreatic Cancer
    Int J Mol Sci.

    Authors : Louis Marstrand-Daucé Lorenzo Diane Anaïs Chassac Nicole Pascal Couvelard Anne Haumaitre Cécile

  • Publication date : 31 May 2023 More

    Efficiency of Orexin-A for Inflammatory Flare and Mucosal Healing in Experimental Colitis: Comparison with the Anti-TNF Alpha Infliximab
    Int J Mol Sci.

    Authors : Anne Blais Annaïg Lan François Blachier Robert Benamouzig Pauline Jouet Couvineau Alain

  • Publication date : 01 April 2023 More

    MALDI Imaging, a Powerful Multiplex Approach to Decipher Intratumoral Heterogeneity: Combined Hepato-Cholangiocarcinomas as Proof of Concept

    Authors : Elia Gigante Cazier Hélène ALBUQUERQUE Miguel Laouirem Samira Beaufrère Aurélie Paradis Valérie

  • Publication date : 01 February 2023 More

    Pathogenesis of primary liver carcinomas
    J Hepatol.

    Authors : Paradis Valérie Jessica Zucman-Rossi

  • Publication date : 16 December 2022 More

    Selective disruption of NRF2-KEAP1 interaction leads to NASH resolution and reduction of liver fibrosis in mice
    JHep Reports

    Authors : Klaus Seedorf Csaba Weber Cedric Vinson Sylvie Berger Laurent-Michel Vuillard Arpad Kiss Stephanie Creusot Olivier Broux Anne Geant Catherine Ilic Karine Lemaitre Johann Richard Hammoutene Adel Julien Mahieux Virginie Martigny Didier Durand Fabien Melchiore Miklos Nyerges Paradis Valérie Nicolas Provost Valérie Duvivier Philippe Delerive

  • Publication date : 01 September 2022 More

    Molecular deciphering of primary liver neuroendocrine neoplasms confirms their distinct existence with foregut-like profile
    J Pathol.

    Authors : De Mestier Louis Nicolle Rémy Poté Nicolas Rebours Vinciane Cauchy François Olivia Hentic Frédérique Maire Ronot Maxime Lebtahi Rachida Sauvanet Alain Paradis Valérie Ruszniewski Philippe Couvelard Anne Cros Jérome

  • Publication date : 28 July 2022 More

    The Orexin receptors: Structural and anti-tumoral properties
    Front Endocrinol (Lausanne).

    Authors : Couvineau Alain Nicole Pascal Gratio Valérie Voisin Thierry

  • Publication date : 25 July 2022 More

    Replication stress triggered by nucleotide pool imbalance drives DNA damage and cGAS-STING pathway activation in NAFLD
    Dev Cell.

    Authors : Romain Donne Maëva Saroul-Ainama Pierre Cordier Hammoutene Adel Christelle Kabore Mira Stadler Ivan Nemazanyy Isabelle Galy-Fauroux Mounia Herrag Tobias Riedl Marie Chansel-Da Cruz Stefano Caruso Stéphanie Bonnafous Rupert Öllinger Roland Rad Kristian Unger Albert Tran Jean-Pierre Couty Philippe Gual Paradis Valérie Séverine Celton-Morizur Mathias Heikenwalder Patrick Revy Chantal Desdouets

  • Publication date : 31 March 2022 More

    Characterization and Pharmacological Validation of a Preclinical Model of NASH in Göttingen Minipigs
    J Clin Exp Hepatol.

    Authors : Valérie Duvivier Stéphanie Creusot Olivier Broux Aurélie Helbert Ludovic Lesage Kevin Moreau Nicolas Lesueur Lindsay Gerard Karine Lemaitre Nicolas Provost Edwige-Ludiwyne Hubert Tania Baltauss Brzustowski Angélique Nathalie De Preville Julia Geronimi Lucie Adoux Franck Letourneur Hammoutene Adel Valla Dominique Paradis Valérie Philippe Delerive

  • Publication date : 11 February 2022 More

    Procollagen C-Proteinase Enhancer-1 (PCPE-1) deficiency in mice reduces liver fibrosis but not NASH progression
    PLoS One.

    Authors : Patricia Sansilvestri Morel Valerie Duvivier Florence Bertin Nicolas Provost Hammoutene Adel Edwige-Ludiwyne Hubert Arantxa Gonzalez Isabelle Tupinon-Mathieu Paradis Valérie Philippe Delerive

  • Publication date : 01 February 2022 More

    Gene expression signature as a surrogate marker of microvascular invasion on routine hepatocellular carcinoma biopsies
    J Hepatol.

    Authors : Beaufrère Aurélie Stefano Caruso Julien Calderaro Poté Nicolas Jean-Charles Bijot Gabielle Couchy Cauchy François Vilgrain Valérie Jessica Zucman-Rossi Paradis Valérie

  • Publication date : 28 November 2021 More

    Orexins: A promising target to digestive cancers, inflammation, obesity and metabolism dysfunctions
    World J Gastroenterol.

    Authors : Couvineau Alain Voisin Thierry Nicole Pascal Gratio Valérie Anne Blais

  • Publication date : 01 July 2021 More

    Transarterial chemoembolisation enhances programmed death-1 and programmed death-ligand 1 expression in hepatocellular carcinoma

    Authors : Ahmed Montasser Beaufrère Aurélie Cauchy François Mohamed Bouattour Soubrane Olivier ALBUQUERQUE Miguel Paradis Valérie

  • Publication date : 29 June 2021 More

    Long-term outcomes following resection of hepatocellular adenomas with small foci of malignant transformation or malignant adenomas
    JHEP Rep.

    Authors : Sophie Chopinet Cauchy François Christian Hobeika Beaufrère Aurélie Poté Nicolas Farges Olivier Dokmak Safi Mohamed Bouattour Ronot Maxime Vilgrain Valérie Paradis Valérie Soubrane Olivier

  • Publication date : 01 May 2021 More

    Insights into the etiology and physiopathology of MODY5/HNF1B pancreatic phenotype with a mouse model of the human disease
    J Pathol.

    Authors : Evans Quilichini Mélanie Fabre Christoffer Nord Thassadite Dirami Axelle Le Marec Silvia Cereghini Raymond C Pasek Maureen Gannon Ulf Ahlgren Haumaitre Cécile

  • Publication date : 11 March 2021 More

    Pancreatic Ductal Adenocarcinoma Arising in Young and Old Patients Displays Similar Molecular Features
    Cancers (Basel) .

    Authors : Raffenne Jérome Fernando A Martin Rémy Nicolle Marina Konta Yuna Blum Jérôme Torrisani Francesco Puleo Jean Baptiste Bachet Magali Svrcek Armel Bardier-Dupas Jean Francois Emile Peter Demetter Miroslav Radman Jean Luc Van Laethem Hammel Pascal Rebours Vinciane Paradis Valérie Couvelard Anne Cros Jérome

  • Publication date : 28 August 2020 More

    Prognostic value of desmoplastic stroma in intrahepatic cholangiocarcinoma
    Modern Pathology.

    Authors : Guedj Nathalie Lorraine Blaise Cauchy François ALBUQUERQUE Miguel Soubrane Olivier Paradis Valérie

  • Publication date : 24 August 2020 More

    New insights into the pathophysiology and clinical care of rare primary liver cancers
    JHEP Rep.

    Authors : Elia Gigante Paradis Valérie Ronot Maxime Cauchy François Soubrane Olivier Nathalie Ganne-Carrié Jean-Charles Nault

  • Publication date : 01 March 2020 More

    A defect in endothelial autophagy occurs in patients with non-alcoholic steatohepatitis and promotes inflammation and fibrosis
    J Hepatol.

    Authors : Hammoutene Adel Biquard Louise Juliette Lasselin Marouane Kheloufi Tanguy Marion Anne-Clémence Vion Jules Mérian Nathalie Colnot Xavier Loyer Alain Tedgui Patrice Codogno Lotersztajn Sophie Paradis Valérie Chantal M Boulanger Rautou Pierre-Emmanuel

  • Publication date : 13 January 2020 More

    The histone acetyltransferase hMOF promotes vascular invasion in hepatocellular carcinoma
    Liver Int.

    Authors : Poté Nicolas Cros Jérome Laouirem Samira Raffenne Jérome Negrão M ALBUQUERQUE Miguel Bedossa Pierre Godinho Ferreira M Ait Si Ali S Fior R Paradis Valérie

  • Publication date : 31 December 2019 More

    Combining imaging and tumour biopsy improves the diagnosis of combined hepatocellular-cholangiocarcinoma
    Liver Int.

    Authors : Gigante E Ronot Maxime Bertin C Ciolina M Bouattour M Dondero F Cauchy F Soubrane Olivier Paradis Valérie

  • Publication date : 20 June 2019 More

    Pancreatic Ductal Deletion of Hnf1b Disrupts Exocrine Homeostasis, Leads to Pancreatitis, and Facilitates Tumorigenesis
    Cell Mol Gastroenterol Hepatol.

    Authors : Evans Quilichini Mélanie Fabre Thassadite Dirami Aline Stedman Matias De Vas Ozge Ozguc Raymond C Pasek Silvia Cereghini Lucie Morillon Carmen Guerra Couvelard Anne Maureen Gannon Haumaitre Cécile

  • Publication date : 01 May 2019 More

    Inter- and intra-tumoural heterogeneity in cancer-associated fibroblasts of human pancreatic ductal adenocarcinoma
    J Pathol.

    Authors : Cindy Neuzillet Annemilaï Tijeras-Raballand Chanthirika Ragulan Cros Jérome Yatish Patil Matthieu Martinet Mert Erkan Jörg Kleeff Jeremy Wilson Minoti Apte Marie Tosolini Abigail S Wilson Francesca R Delvecchio Corinne Bousquet Paradis Valérie Hammel Pascal Anguraj Sadanandam Hemant M Kocher

  • Publication date : 21 January 2019 More

    Prognostic Biomarkers in Pancreatic Cancer: Avoiding Errata When Using the TCGA Dataset
    Cancers (Basel).

    Authors : Nicolle Rémy Raffenne Jérome Paradis Valérie Couvelard Anne Aurelien de Reynies Yuna Blum Cros Jérome

  • Publication date : 18 August 2018 More

    Ectopic expression of OX1R in ulcerative colitis mediates anti-inflammatory effect of orexin-A.
    Biochim Biophys Acta Mol Basis Dis.

    Authors : Messal N Fernandez N Dayot Stephanie Gratio Valérie Nicole Pascal Prochasson C Chantret Isabelle LeGuilloux G Jarry A Couvelard Anne Treton Xavier Voisin Thierry Ogier-Denis Eric Couvineau Alain


Site de référence pour les Appels à Projets

Les dernières publications marquantes

  • Publication date : 01 May 2024 More

    Food additive emulsifiers and the risk of type 2 diabetes: analysis of data from the NutriNet-Santé prospective cohort study
    Lancet Diabetes Endocrinol.

    Authors : Clara Salame Guillaume Javaux Laury Sellem Viennois Emilie Fabien Szabo de Edelenyi Cédric Agaësse Alexandre De Sa Inge Huybrechts Fabrice Pierre Xavier Coumoul Chantal Julia Emmanuelle Kesse-Guyot Benjamin Allès Léopold K Fezeu Serge Hercberg Mélanie Deschasaux-Tanguy Emmanuel Cosson Sopio Tatulashvili Benoit Chassaing Bernard Srour Mathilde Touvier

  • Publication date : 09 April 2024 More

    Prognosis algorithms for acute decompensation of cirrhosis and ACLF
    Liver Int.

    Authors : Valainathan Shantha Qing Xie Vicente Arroyo Rautou Pierre-Emmanuel

  • Publication date : 01 March 2024 More

    Hepatocellular carcinoma in patients with non-alcoholic fatty liver disease is associated with heterogeneous pattern of fat infiltration in skeletal muscles
    Eur Radiol.

    Authors : Maxime Nachit Dioguardi Burgio Marco Abyzov Anton Garteiser Philippe Paradis Valérie Vilgrain Valérie Isabelle Leclercq Van Beers Bernard