Leader
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Paradis Valérie
- 01 40 87 54 63
- valerie.paradis@bjn.aphp.fr
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Couvineau Alain
- 01 57 27 74 88
- alain.Couvineau@inserm.fr
From inflammation to cancer in digestive diseases (INDiD)
Team Paradis / Couvineau
Department Hepato-Gastroenterology Department
Line-up
Permanent scientific
PhD student
Student
Research assistant
proteomics
Presentation
This project results of the merging of 3 research teams from the past 5-years contract and aims to investigate specific aspects of the physiopathology of the sequence inflammation-cancer in digestive tract, identify new diagnostic markers and develop innovative therapeutic targets. First axis, focusing on liver carcinogenesis related to metabolic syndrome, will identify the specific mechanisms involved in inflammatory liver damages by favoring original in situ molecular approaches such as mass spectrometry imaging (MSI). The contribution of lipid environment (liver or visceral adipose tissue) in the progression to hepatocellular carcinoma (HCC) will also be investigated. Second axis will provide new insights in the role of GPCR in the progression of digestive cancers, which will allow the development of new therapeutic strategies. We will focus on (1) orexins and their receptors (OXR) which induce a robust apoptosis in digestive cancers, and (2) CXCR4 which confers survival, invasion potential to cancer cells. We will be especially interested to evaluate potential effects of these targets in preclinical models of digestive cancers that have developed resistance to conventional cytotoxic or targeted therapies.
Research projects:
Work package: Inflammation, fibrosis and cancer in the liver
Metabolic syndrome (MS) is becoming the leading cause of chronic liver diseases worldwide and may result in the development of chronic liver diseases and hepatocellular carcinoma (HCC). Progression of liver carcinogenicity in MS is complex, involving the development of tissue damages (steatosis and fibrosis) and also an inflammatory systemic background through adipokines production from visceral adipose tissue
Our project aims:
- To study the molecular mechanisms involved in the development of early liver damage related to MS (steatosis and steatohepatitis) which start in centrolobular area. The liver lipidomic pattern will be determined by an in situ approach. This study will allow to identify profibrogenic mediators specifically induced in the liver damage progression observed in MS. The functional role of fibrogenesis will estimated by using cell co-culture models (liver stellar cells/hepatocytes/endothelial cells).
- To decipher the specific molecular mechanisms involved in tumor progression associated to MS by the determination of the role of visceral adipose tissue (VAT) through the production of Fatty Acid Binging Proteins (FABPs) and lipid chaperones which are involved in the fatty acid trafficking. The role of pro-oncogenic of FABP4 will determined using in vitro and in vivo experimental models. Moreover, we will examine the impact of tissue modifications in the peritumoral hepatic parenchyma on HCC development by using in situ proteomic and lipidomic approaches. In this context, we will evaluate the anti-tumoral effects of putative therapeutical targets including the metformine.
This project will be based on the development of innovative technologies including mass spectrometry imaging (MALDI imaging), tissue culture models (ex vivo models) and animal models which reproduced liver damages related to MS (High fat diet, fructose diet …). The determination of molecular species identified by MALDI was carried out in collaboration with JM Camadro’s group (Institut J. Monod, Paris).
Work package: GPCRs and digestive cancers (Couvineau Alain’s group)
Since few years ago, drugs targeting G protein-coupled receptors GPCRs are shown to have excellent therapeutic benefits. In this context, our project is to study the role and clinical interest of GPCRs in particular orexin receptors (OXR), in digestive cancer development. Orexins, hypothalamic peptides, interacted with two GPCR (OX1R and OX2R). They regulate sleep, wakefulness, feeding, breathing, reward system, or drug addiction. We have shown that orexins induced a robust apoptosis in colon cancer cell lines which expressed OX1R. This cell death was mediated through ITIM sequence resulting in the recruitment and theactivation of the SHP-2, leading to a mitochondrial apoptosis. Furthermore, we have demonstrated that OX1R is aberrantly expressed in digestive cancers including colon cancers, pancreas cancers and liver cancers but inversely is not present in normal tissue. Moreover we have demonstrated that orexins have strong anti-tumoral effects in pre-clinical models of digestive cancers.
Our project aims:
- To study the presence of of orexins and theirreceptors in various pre-cancerous and inflammatory states in the digestive tract, especially in the early stage of colonic and pancreatic carcinogenesis encompassing IBD and adenomas (polyps, PanIN). To evaluate the dynamic role of OX1R during the carcinogenesis, we will use various mouse models such as chemically colitis- induced mice (DSS) and/or genetically modified mice as EXCY2 model (E. Ogier-Denis, Paris) or IL10-/- (A. Jarry, Nantes) which develop spontaneously colitis-associated cancer. Xenografted models produced from patient resected tumors (xenograft derived patient, PDX) are currently in progress OX1R expression in pancreatic adenocarcinoma
- To study the role of orexins on isolated cells and/or tumors explants maintained in culture from resected patient tumors (colon, pancreas and liver). This innovative approach developed in our team, will allow us to determine the anti-tumoral effect of orexins ex vivo by measuring various markers of apoptosis, hypoxia and angiogenesis.
- To study the OX1R signaling pathways in which the recruitment of SHP2 and oxidative stress activation (p38, ROS, NRF2….) induces a mitochondrial apoptosis leading to anti-tumoral effects of orexins and also their anti-inflammatory properties.
- To define the structure-function relationships of orexins and OX1R in order to develop new agonists having a therapeutical interest in the treatment of digestive cancers (colon, pancreas and liver). Indeed, the determination of residues involving in the interaction between orexins and OX1R using alanine-scanning, side directed mutagenesis associated to 3D molecular modeling approaches will allow us to design, in collaboration with pharmaceutical industry, new molecules. Moreover, alternative strategies such as the production of antibodies mimicking the agonist properties of orexins will be planned Anti-tumoral effect of orexins in xenografted colon cancer cell line (HT-29)
This project could lead :
- To decipher the role of a number of GPCRs including OX receptor in the induction of apoptosis processes;
- To define the potential role of orexins in the treatment of digestive cancers and IBD;
- To design innovative molecules having therapeutical interest.
3D model of OX1R
Landmark publications
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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
Autors : 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
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Publication date : 01 September 2022 More
Molecular deciphering of primary liver neuroendocrine neoplasms confirms their distinct existence with foregut-like profile
J Pathol.
Autors : 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
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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.
Autors : 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
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Publication date : 31 March 2022 More
Characterization and Pharmacological Validation of a Preclinical Model of NASH in Göttingen Minipigs
J Clin Exp Hepatol.
Autors : 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
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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.
Autors : Patricia Sansilvestri Morel Valerie Duvivier Florence Bertin Nicolas Provost Hammoutene Adel Edwige-Ludiwyne Hubert Arantxa Gonzalez Isabelle Tupinon-Mathieu Paradis Valérie Philippe Delerive
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Publication date : 01 February 2022 More
Gene expression signature as a surrogate marker of microvascular invasion on routine hepatocellular carcinoma biopsies
J Hepatol.
Autors : Beaufrère Aurélie Stefano Caruso Julien Calderaro Poté Nicolas Jean-Charles Bijot Gabielle Couchy Cauchy François Vilgrain Valérie Jessica Zucman-Rossi Paradis Valérie
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Publication date : 28 November 2021 More
Orexins: A promising target to digestive cancers, inflammation, obesity and metabolism dysfunctions
World J Gastroenterol.
Autors : Couvineau Alain Voisin Thierry Nicole Pascal Gratio Valérie Anne Blais
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Publication date : 01 July 2021 More
Transarterial chemoembolisation enhances programmed death-1 and programmed death-ligand 1 expression in hepatocellular carcinoma
Histopathology.
Autors : Ahmed Montasser Beaufrère Aurélie Cauchy François Mohamed Bouattour Soubrane Olivier ALBUQUERQUE Miguel Paradis Valérie
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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.
Autors : Sophie Chopinet Cauchy François Christian Hobeika Beaufrère Aurélie Poté Nicolas Farges Olivier Dokmak Safi Mohamed Bouattour Ronot Maxime Vilgrain Valérie Paradis Valérie Soubrane Olivier
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Publication date : 11 March 2021 More
Pancreatic Ductal Adenocarcinoma Arising in Young and Old Patients Displays Similar Molecular Features
Cancers (Basel) .
Autors : 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
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Publication date : 28 August 2020 More
Prognostic value of desmoplastic stroma in intrahepatic cholangiocarcinoma
Modern Pathology.
Autors : Guedj Nathalie Lorraine Blaise Cauchy François ALBUQUERQUE Miguel Soubrane Olivier Paradis Valérie
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Publication date : 24 August 2020 More
New insights into the pathophysiology and clinical care of rare primary liver cancers
JHEP Rep.
Autors : Elia Gigante Paradis Valérie Ronot Maxime Cauchy François Soubrane Olivier Nathalie Ganne-Carrié Jean-Charles Nault
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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.
Autors : 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
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Publication date : 13 January 2020 More
The histone acetyltransferase hMOF promotes vascular invasion in hepatocellular carcinoma
Liver Int.
Autors : 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
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Publication date : 31 December 2019 More
Combining imaging and tumour biopsy improves the diagnosis of combined hepatocellular-cholangiocarcinoma
Liver Int.
Autors : Gigante E Ronot Maxime Bertin C Ciolina M Bouattour M Dondero F Cauchy F Soubrane Olivier Paradis Valérie
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Publication date : 01 May 2019 More
Inter- and intra-tumoural heterogeneity in cancer-associated fibroblasts of human pancreatic ductal adenocarcinoma
J Pathol.
Autors : 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
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Publication date : 01 April 2019 More
Endothelial fatty liver binding protein 4: a new targetable mediator in hepatocellular carcinoma related to metabolic syndrome.
Oncogene.
Autors : Laouirem Samira Sannier A Norkowski E Cauchy F Doblas Sabrina Rautou Pierre-Emmanuel ALBUQUERQUE Miguel Garteiser Philippe Sognigbé L Raffenne Jérome Van Beers Bernard Soubrane Olivier Bedossa Pierre Cros Jérome Paradis Valérie
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Publication date : 21 January 2019 More
Prognostic Biomarkers in Pancreatic Cancer: Avoiding Errata When Using the TCGA Dataset
Cancers (Basel).
Autors : Nicolle Rémy Raffenne Jérome Paradis Valérie Couvelard Anne Aurelien de Reynies Yuna Blum Cros Jérome
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Publication date : 01 January 2019 More
Proteomic Landscape of Cholangiocarcinomas Reveals Three Different Subgroups According to Their Localization and the Aspect of Non-Tumor Liver.
Proteomics Clin Appl.
Autors : Le Faouder Julie Gigante E Léger T ALBUQUERQUE Miguel Beaufrère A Soubrane Olivier Dokmak S Camadro JM Cros Jérome Paradis Valérie
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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.
Autors : 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
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Publication date : 01 April 2018 More
Contribution of virtual biopsy to the screening of microvascular invasion in hepatocellular carcinoma: A pilot study
Liver Int.
Autors : Poté Nicolas Cauchy François ALBUQUERQUE Miguel Cros Jérome Soubrane Olivier Bedossa Pierre Paradis Valérie