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1. Deep learning-based phenotyping reclassifies combined hepatocellular-cholangiocarcinoma

Author

Julien Calderaro, Narmin Ghaffari Laleh, Qinghe Zeng, Pascale Maille, Loetitia Favre, Anaïs Pujals, Christophe Klein, Céline Bazille, Lara R. Heij, Arnaud Uguen, Tom Luedde, Luca Di Tommaso, Aurélie Beaufrère, Augustin Chatain, Delphine Gastineau, Cong Trung Nguyen, Hiep Nguyen-Canh, Khuyen Nguyen Thi, Viviane Gnemmi, Rondell P. Graham, Frédéric Charlotte, Dominique Wendum, Mukul Vij, Daniela S. Allende, Federico Aucejo, Alba Diaz, Benjamin Rivière, Astrid Herrero, Katja Evert, Diego Francesco Calvisi, Jérémy Augustin, Wei Qiang Leow, Howard Ho Wai Leung, Emmanuel Boleslawski, Mohamed Rela, Arnaud François, Anthony Wing-Hung Cha, Alejandro Forner, Maria Reig, Manon Allaire, Olivier Scatton, Denis Chatelain, Camille Boulagnon-Rombi, Nathalie Sturm, Benjamin Menahem, Eric Frouin, David Tougeron, Christophe Tournigand, Emmanuelle Kempf, Haeryoung Kim, Massih Ningarhari, Sophie Michalak-Provost, Purva Gopal, Raffaele Brustia, Eric Vibert, Kornelius Schulze, Darius F. Rüther, Sören A. Weidemann, Rami Rhaiem, Jean-Michel Pawlotsky, Xuchen Zhang, Alain Luciani, Sébastien Mulé, Alexis Laurent, Giuliana Amaddeo, Hélène Regnault, Eleonora De Martin, Christine Sempoux, Pooja Navale, Maria Westerhoff, Regina Cheuk-Lam Lo, Jan Bednarsch, Annette Gouw, Catherine Guettier, Marie Lequoy, Kenichi Harada, Pimsiri Sripongpun, Poowadon Wetwittayaklang, Nicolas Loménie, Jarukit Tantipisit, Apichat Kaewdech, Jeanne Shen, Valérie Paradis, Stefano Caruso, and Jakob Nikolas Kather

Subjects
Science
Abstract

Abstract Primary liver cancer arises either from hepatocytic or biliary lineage cells, giving rise to hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICCA). Combined hepatocellular- cholangiocarcinomas (cHCC-CCA) exhibit equivocal or mixed features of both, causing diagnostic uncertainty and difficulty in determining proper management. Here, we perform a comprehensive deep learning-based phenotyping of multiple cohorts of patients. We show that deep learning can reproduce the diagnosis of HCC vs. CCA with a high performance. We analyze a series of 405 cHCC-CCA patients and demonstrate that the model can reclassify the tumors as HCC or ICCA, and that the predictions are consistent with clinical outcomes, genetic alterations and in situ spatial gene expression profiling. This type of approach could improve treatment decisions and ultimately clinical outcome for patients with rare and biphenotypic cancers such as cHCC-CCA.

Published
2023
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2. Protective potential of the gallbladder in primary sclerosing cholangitis

Author

Nora Cazzagon, Ester Gonzalez-Sanchez, Haquima El-Mourabit, Dominique Wendum, Dominique Rainteau, Lydie Humbert, Christophe Corpechot, Olivier Chazouillères, Lionel Arrivé, Chantal Housset, and Sara Lemoinne

Subjects
Abcb4 knockout mice, Bile acids, Cholecystectomy, Gallbladder volume, Magnetic resonance imaging, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Background & Aims: Gallbladder enlargement is common in patients with primary sclerosing cholangitis (PSC). The gallbladder may confer hepatoprotection against bile acid overload, through the sequestration and cholecystohepatic shunt of bile acids. The aim of this study was to assess the potential impact of the gallbladder on disease features and bile acid homeostasis in PSC. Methods: Patients with PSC from a single tertiary center who underwent liver MRI with three-dimensional cholangiography and concomitant analyses of serum bile acids were included. Gallbladder volume was measured by MRI and a cut-off of 50 ml was used to define gallbladder enlargement. Bile acid profiles and PSC severity, as assessed by blood tests and MRI features, were compared among patients according to gallbladder size (enlarged vs. normal-sized) or presence (removed vs. conserved). The impact of cholecystectomy was also assessed in the Abcb4 knockout mouse model of PSC. Results: Sixty-one patients with PSC, all treated with ursodeoxycholic acid (UDCA), were included. The gallbladder was enlarged in 30 patients, whereas 11 patients had been previously cholecystectomized. Patients with enlarged gallbladders had significantly lower alkaline phosphatase, a lower tauro-vs. glycoconjugate ratio and a higher UDCA vs. total bile acid ratio compared to those with normal-sized gallbladders. In addition, gallbladder volume negatively correlated with the hydrophobicity index of bile acids. Cholecystectomized patients displayed significantly higher aspartate aminotransferase and more severe bile duct strictures and dilatations compared to those with conserved gallbladder. In the Abcb4 knockout mice, cholecystectomy caused an increase in hepatic bile acid content and in circulating secondary bile acids, and an aggravation in cholangitis, inflammation and liver fibrosis. Conclusion: Altogether, our findings indicate that the gallbladder fulfills protective functions in PSC. Impact and implications: In patients with primary sclerosing cholangitis (PSC), gallbladder status impacts on bile acid homeostasis and disease features. We found evidence of lessened bile acid toxicity in patients with PSC and enlarged gallbladders and of increased disease severity in those who were previously cholecystectomized. In the Abcb4 knockout mouse model of PSC, cholecystectomy causes an aggravation of cholangitis and liver fibrosis. Overall, our results suggest that the gallbladder plays a protective role in PSC.

Published
2023
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3. Diet‐Induced Dysbiosis and Genetic Background Synergize With Cystic Fibrosis Transmembrane Conductance Regulator Deficiency to Promote Cholangiopathy in Mice

Author

Dominique Debray, Haquima El Mourabit, Fatiha Merabtene, Loïc Brot, Damien Ulveling, Yves Chrétien, Dominique Rainteau, Ivan Moszer, Dominique Wendum, Harry Sokol, and Chantal Housset

Subjects
Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

The most typical expression of cystic fibrosis (CF)–related liver disease is a cholangiopathy that can progress to cirrhosis. We aimed to determine the potential impact of environmental and genetic factors on the development of CF‐related cholangiopathy in mice. Cystic fibrosis transmembrane conductance regulator (Cftr)−/− mice and Cftr+/+ littermates in a congenic C57BL/6J background were fed a high medium‐chain triglyceride (MCT) diet. Liver histopathology, fecal microbiota, intestinal inflammation and barrier function, bile acid homeostasis, and liver transcriptome were analyzed in 3‐month‐old males. Subsequently, MCT diet was changed for chow with polyethylene glycol (PEG) and the genetic background for a mixed C57BL/6J;129/Ola background (resulting from three backcrosses), to test their effect on phenotype. C57BL/6J Cftr−/− mice on an MCT diet developed cholangiopathy features that were associated with dysbiosis, primarily Escherichia coli enrichment, and low‐grade intestinal inflammation. Compared with Cftr+/+ littermates, they displayed increased intestinal permeability and a lack of secondary bile acids together with a low expression of ileal bile acid transporters. Dietary‐induced (chow with PEG) changes in gut microbiota composition largely prevented the development of cholangiopathy in Cftr−/− mice. Regardless of Cftr status, mice in a mixed C57BL/6J;129/Ola background developed fatty liver under an MCT diet. The Cftr−/− mice in the mixed background showed no cholangiopathy, which was not explained by a difference in gut microbiota or intestinal permeability, compared with congenic mice. Transcriptomic analysis of the liver revealed differential expression, notably of immune‐related genes, in mice of the congenic versus mixed background. In conclusion, our findings suggest that CFTR deficiency causes abnormal intestinal permeability, which, combined with diet‐induced dysbiosis and immune‐related genetic susceptibility, promotes CF‐related cholangiopathy.

Published
2018
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4. Diagnosing Nodular Regenerative Hyperplasia of the Liver Is Thwarted by Low Interobserver Agreement.

Author

Bindia Jharap, Dirk P van Asseldonk, Nanne K H de Boer, Pierre Bedossa, Joachim Diebold, A Mieke Jonker, Emmanuelle Leteurtre, Joanne Verheij, Dominique Wendum, Fritz Wrba, Pieter E Zondervan, Jean-Frédéric Colombel, Walter Reinisch, Chris J J Mulder, Elisabeth Bloemena, Adriaan A van Bodegraven, and NRH-Pathology Investigators

Subjects
Medicine, Science
Abstract

Nodular regenerative hyperplasia (NRH) of the liver is associated with several diseases and drugs. Clinical symptoms of NRH may vary from absence of symptoms to full-blown (non-cirrhotic) portal hypertension. However, diagnosing NRH is challenging. The objective of this study was to determine inter- and intraobserver agreement on the histopathologic diagnosis of NRH.Liver specimens (n=48) previously diagnosed as NRH, were reviewed for the presence of NRH by seven pathologists without prior knowledge of the original diagnosis or clinical background. The majority of the liver specimens were from thiopurine using inflammatory bowel disease patients. Histopathologic features contributing to NRH were also assessed. Criteria for NRH were modified by consensus and subsequently validated. Interobserver agreement was evaluated by using the standard kappa index.After review, definite NRH, inconclusive NRH and no NRH were found in 35% (23-40%), 21% (13-27%) and 44% (38-56%), respectively (median, IQR). The median interobserver agreement for NRH was poor (κ = 0.20, IQR 0.14-0.28). The intraobserver variability on NRH ranged between 14% and 71%. After modification of the criteria and exclusion of biopsies with technical shortcomings, the interobserver agreement on the diagnosis NRH was fair (κ = 0.45).The interobserver agreement on the histopathologic diagnosis of NRH was poor, even when assessed by well-experienced liver pathologists. Modification of the criteria of NRH based on consensus effort and exclusion of biopsies of poor quality led to a fairly increased interobserver agreement. The main conclusion of this study is that NRH is a clinicopathologic diagnosis that cannot reliably be based on histopathology alone.

Published
2015
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6. Data from The IGF2/IR/IGF1R Pathway in Tumor Cells and Myofibroblasts Mediates Resistance to EGFR Inhibition in Cholangiocarcinoma

Author

Laura Fouassier, Françoise Praz, Christèle Desbois-Mouthon, Chantal Housset, Cédric Coulouarn, Dominique Wendum, Fatiha Merabtene, Martine Mergey, Audrey Clapéron, Sylvana Tahraoui, Cindy Lobe, and Javier Vaquero

Abstract

Purpose: Cholangiocarcinoma (CCA) is a desmoplastic tumor of the biliary tree in which epidermal growth factor receptor (EGFR) is overexpressed and contributes to cancer progression. Although EGFR has been envisaged as a target for therapy, treatment with tyrosine kinase inhibitors (TKI) such as erlotinib did not provide therapeutic benefit in patients with CCA, emphasizing the need to investigate resistance mechanisms against EGFR inhibition.Experimental Design: Resistant CCA cells to EGFR inhibition were obtained upon long-time exposure of cells with erlotinib. Cell signaling, viability, migration, and spheroid growth were determined in vitro, and tumor growth was evaluated in CCA xenograft models.Results: Erlotinib-resistant CCA cells displayed metastasis-associated signatures that correlated with a marked change in cell plasticity associated with an epithelial–mesenchymal transition (EMT) and a cancer stem cell (CSC)–like phenotype. Resistant cells exhibited an upregulation of insulin receptor (IR) and insulin-like growth factor (IGF) 1 receptor (IGF1R), along with an increase in IGF2 expression. IR/IGF1R inhibition reduced EMT and CSC-like traits in resistant cells. In vivo, tumors developed from resistant CCA cells were larger and exhibited a more prominent stromal compartment, enriched in cancer-associated fibroblasts (CAF). Pharmacological coinhibition of EGFR and IR/IGF1R reduced tumor growth and stromal compartment in resistant tumors. Modeling of CCA-CAF crosstalk showed that IGF2 expressed by fibroblasts boosted IR/IGF1R signaling in resistant cells. Furthermore, IR/IGF1R signaling positively regulated fibroblast proliferation and activation.Conclusions: To escape EGFR-TKI treatment, CCA tumor cells develop an adaptive mechanism by undergoing an IR/IGF1R-dependent phenotypic switch, involving a contribution of stromal cells. Clin Cancer Res; 24(17); 4282–96. ©2018 AACR.

Published
2023

7. Supplementary Data from The IGF2/IR/IGF1R Pathway in Tumor Cells and Myofibroblasts Mediates Resistance to EGFR Inhibition in Cholangiocarcinoma

Author

Laura Fouassier, Françoise Praz, Christèle Desbois-Mouthon, Chantal Housset, Cédric Coulouarn, Dominique Wendum, Fatiha Merabtene, Martine Mergey, Audrey Clapéron, Sylvana Tahraoui, Cindy Lobe, and Javier Vaquero

Abstract

Supplementary Table 1. Human primers used for quantitative real-time PCR. Supplementary Table 2. Mouse primers used for quantitative real-time PCR. Supplementary Table 3. Human primers used for analysis of IR-A and IR-B isoforms by PCR visualized on gel electrophoresis. Supplementary Table 4. Primary antibodies used for immunodetection. Supplementary Table 5. Clinical and pathological characteristics of patients with CCA (n=10) Supplementary Table 6. Cancer stem cell-associated gene sets significantly enriched in the gene profiles of erlotinib-resistant cell lines. Supplementary Figure S1. Resistant CCA cells to EGFR inhibition display a down-regulation of activated EGFR and a lower sensitivity to erlotinib. Supplementary Figure S2. EGI-1 cells resistant to EGFR inhibition display increased migratory properties. Supplementary Figure S3. IGF2/IR/IGF1R axis is an escape route upregulated in CCA cells resistant to EGFR inhibition. Supplementary Figure S4. IR/IGF1R blockage regulates viability and cell plasticity of cholangiocarcinoma cells resistant to EGFR inhibition. Supplementary Figure S5. IR/IGF1R downregulation regulates viability and cell plasticity of cholangiocarcinoma cells resistant to EGFR inhibition. Supplementary Figure S6. Cholangiocarcinoma cells resistant to EGFR inhibition show increased tumorigenic potential and higher tumor stroma content. Supplementary Figure S7. Tumor cells and CAFs express IGF2 and IGF1R in human intrahepatic CCA. Supplementary Figure S8. IGF2/IR/IGF1R signaling regulates proliferation of hepatic myofibroblasts.

Published
2023

8. Supplementary Figure S5 from Mitogenic Insulin Receptor-A Is Overexpressed in Human Hepatocellular Carcinoma due to EGFR-Mediated Dysregulation of RNA Splicing Factors

Author

Christèle Desbois-Mouthon, Olivier Rosmorduc, Chantal Housset, Françoise Praz, Filomena Conti, Olivier Soubrane, Olivier Scatton, Colette Rey, Yves Chrétien, Audrey Clapéron, Dominique Wendum, Lynda Aoudjehane, Laetitia Fartoux, and Hamza Chettouh

Abstract

Supplementary Figure S5 - PDF file 190K, The blockage of EGFR signalling does not alter the subcellular localization of splicing factors in HCC cells

Published
2023

9. Supplementary Figure 3 from Implication of Metastasis Suppressor NM23-H1 in Maintaining Adherens Junctions and Limiting the Invasive Potential of Human Cancer Cells

Author

Marie-Lise Lacombe, Christian Gespach, Philippe Chavrier, Marc Bracke, Philippe Birembaut, Béatrice Nawrocki-Raby, Sylvie Dufour, Christèle Desbois-Mouthon, Nicolas Chignard, Renaud Poincloux, Dominique Wendum, Floria Lizarraga, Olivier De Wever, and Mathieu Boissan

Abstract

Supplementary Figure 3 from Implication of Metastasis Suppressor NM23-H1 in Maintaining Adherens Junctions and Limiting the Invasive Potential of Human Cancer Cells

Published
2023

10. Supplementary Figure 11 from Implication of Metastasis Suppressor NM23-H1 in Maintaining Adherens Junctions and Limiting the Invasive Potential of Human Cancer Cells

Author

Marie-Lise Lacombe, Christian Gespach, Philippe Chavrier, Marc Bracke, Philippe Birembaut, Béatrice Nawrocki-Raby, Sylvie Dufour, Christèle Desbois-Mouthon, Nicolas Chignard, Renaud Poincloux, Dominique Wendum, Floria Lizarraga, Olivier De Wever, and Mathieu Boissan

Abstract

Supplementary Figure 11 from Implication of Metastasis Suppressor NM23-H1 in Maintaining Adherens Junctions and Limiting the Invasive Potential of Human Cancer Cells

Published
2023

11. Supplementary Figure Legends 1-11, Methods from Implication of Metastasis Suppressor NM23-H1 in Maintaining Adherens Junctions and Limiting the Invasive Potential of Human Cancer Cells

Author

Marie-Lise Lacombe, Christian Gespach, Philippe Chavrier, Marc Bracke, Philippe Birembaut, Béatrice Nawrocki-Raby, Sylvie Dufour, Christèle Desbois-Mouthon, Nicolas Chignard, Renaud Poincloux, Dominique Wendum, Floria Lizarraga, Olivier De Wever, and Mathieu Boissan

Abstract

Supplementary Figure Legends 1-11, Methods from Implication of Metastasis Suppressor NM23-H1 in Maintaining Adherens Junctions and Limiting the Invasive Potential of Human Cancer Cells

Published
2023

12. Supplementary Figure 9 from Implication of Metastasis Suppressor NM23-H1 in Maintaining Adherens Junctions and Limiting the Invasive Potential of Human Cancer Cells

Author

Marie-Lise Lacombe, Christian Gespach, Philippe Chavrier, Marc Bracke, Philippe Birembaut, Béatrice Nawrocki-Raby, Sylvie Dufour, Christèle Desbois-Mouthon, Nicolas Chignard, Renaud Poincloux, Dominique Wendum, Floria Lizarraga, Olivier De Wever, and Mathieu Boissan

Abstract

Supplementary Figure 9 from Implication of Metastasis Suppressor NM23-H1 in Maintaining Adherens Junctions and Limiting the Invasive Potential of Human Cancer Cells

Published
2023

13. Data from Mitogenic Insulin Receptor-A Is Overexpressed in Human Hepatocellular Carcinoma due to EGFR-Mediated Dysregulation of RNA Splicing Factors

Author

Christèle Desbois-Mouthon, Olivier Rosmorduc, Chantal Housset, Françoise Praz, Filomena Conti, Olivier Soubrane, Olivier Scatton, Colette Rey, Yves Chrétien, Audrey Clapéron, Dominique Wendum, Lynda Aoudjehane, Laetitia Fartoux, and Hamza Chettouh

Abstract

Insulin receptor (IR) exists as two isoforms resulting from the alternative splicing of IR pre-mRNA. IR-B promotes the metabolic effects of insulin, whereas IR-A rather signals proliferative effects. IR-B is predominantly expressed in the adult liver. Here, we show that the alternative splicing of IR pre-mRNA is dysregulated in a panel of 85 human hepatocellular carcinoma (HCC) while being normal in adjacent nontumor liver tissue. An IR-B to IR-A switch is frequently observed in HCC tumors regardless of tumor etiology. Using pharmacologic and siRNA approaches, we show that the autocrine or paracrine activation of the EGF receptor (EGFR)/mitogen-activated protein/extracellular signal–regulated kinase pathway increases the IR-A:IR-B ratio in HCC cell lines, but not in normal hepatocytes, by upregulating the expression of the splicing factors CUGBP1, hnRNPH, hnRNPA1, hnRNPA2B1, and SF2/ASF. In HCC tumors, there is a significant correlation between the expression of IR-A and that of splicing factors. Dysregulation of IR pre-mRNA splicing was confirmed in a chemically induced model of HCC in rat but not in regenerating livers after partial hepatectomy. This study identifies a mechanism responsible for the generation of mitogenic IR-A and provides a novel interplay between IR and EGFR pathways in HCC. Increased expression of IR-A during neoplastic transformation of hepatocytes could mediate some of the adverse effects of hyperinsulinemia on HCC. Cancer Res; 73(13); 3974–86. ©2013 AACR.

Published
2023

14. Supplementary Figure 7 from Implication of Metastasis Suppressor NM23-H1 in Maintaining Adherens Junctions and Limiting the Invasive Potential of Human Cancer Cells

Author

Marie-Lise Lacombe, Christian Gespach, Philippe Chavrier, Marc Bracke, Philippe Birembaut, Béatrice Nawrocki-Raby, Sylvie Dufour, Christèle Desbois-Mouthon, Nicolas Chignard, Renaud Poincloux, Dominique Wendum, Floria Lizarraga, Olivier De Wever, and Mathieu Boissan

Abstract

Supplementary Figure 7 from Implication of Metastasis Suppressor NM23-H1 in Maintaining Adherens Junctions and Limiting the Invasive Potential of Human Cancer Cells

Published
2023

15. Supplementary Tables S1-S5 from Mitogenic Insulin Receptor-A Is Overexpressed in Human Hepatocellular Carcinoma due to EGFR-Mediated Dysregulation of RNA Splicing Factors

Author

Christèle Desbois-Mouthon, Olivier Rosmorduc, Chantal Housset, Françoise Praz, Filomena Conti, Olivier Soubrane, Olivier Scatton, Colette Rey, Yves Chrétien, Audrey Clapéron, Dominique Wendum, Lynda Aoudjehane, Laetitia Fartoux, and Hamza Chettouh

Abstract

Supplementary Tables S1-S5 - PDF file 94K, Clinicopathologic characteristics of patients with HCC (S1); Pharmacological inhibitors (S2); Antibodies for Western blot and immunofluorescence (S3); Primer pairs for qualitative and quantitative PCR (S4); Correlations between IR-A and splicing factor mRNA levels in human HCC tumours (S5)

Published
2023

16. Supplementary Figure 6 from Implication of Metastasis Suppressor NM23-H1 in Maintaining Adherens Junctions and Limiting the Invasive Potential of Human Cancer Cells

Author

Marie-Lise Lacombe, Christian Gespach, Philippe Chavrier, Marc Bracke, Philippe Birembaut, Béatrice Nawrocki-Raby, Sylvie Dufour, Christèle Desbois-Mouthon, Nicolas Chignard, Renaud Poincloux, Dominique Wendum, Floria Lizarraga, Olivier De Wever, and Mathieu Boissan

Abstract

Supplementary Figure 6 from Implication of Metastasis Suppressor NM23-H1 in Maintaining Adherens Junctions and Limiting the Invasive Potential of Human Cancer Cells

Published
2023

17. Supplementary Movie 2 from Implication of Metastasis Suppressor NM23-H1 in Maintaining Adherens Junctions and Limiting the Invasive Potential of Human Cancer Cells

Author

Marie-Lise Lacombe, Christian Gespach, Philippe Chavrier, Marc Bracke, Philippe Birembaut, Béatrice Nawrocki-Raby, Sylvie Dufour, Christèle Desbois-Mouthon, Nicolas Chignard, Renaud Poincloux, Dominique Wendum, Floria Lizarraga, Olivier De Wever, and Mathieu Boissan

Abstract

Supplementary Movie 2 from Implication of Metastasis Suppressor NM23-H1 in Maintaining Adherens Junctions and Limiting the Invasive Potential of Human Cancer Cells

Published
2023

18. Supplementary Figure Legends from Mitogenic Insulin Receptor-A Is Overexpressed in Human Hepatocellular Carcinoma due to EGFR-Mediated Dysregulation of RNA Splicing Factors

Author

Christèle Desbois-Mouthon, Olivier Rosmorduc, Chantal Housset, Françoise Praz, Filomena Conti, Olivier Soubrane, Olivier Scatton, Colette Rey, Yves Chrétien, Audrey Clapéron, Dominique Wendum, Lynda Aoudjehane, Laetitia Fartoux, and Hamza Chettouh

Abstract

Supplementary Figure Legends - PDF file 119K, Legend for Supplementary Figures S1-S6

Published
2023

19. Supplementary Figure 5 from Implication of Metastasis Suppressor NM23-H1 in Maintaining Adherens Junctions and Limiting the Invasive Potential of Human Cancer Cells

Author

Marie-Lise Lacombe, Christian Gespach, Philippe Chavrier, Marc Bracke, Philippe Birembaut, Béatrice Nawrocki-Raby, Sylvie Dufour, Christèle Desbois-Mouthon, Nicolas Chignard, Renaud Poincloux, Dominique Wendum, Floria Lizarraga, Olivier De Wever, and Mathieu Boissan

Abstract

Supplementary Figure 5 from Implication of Metastasis Suppressor NM23-H1 in Maintaining Adherens Junctions and Limiting the Invasive Potential of Human Cancer Cells

Published
2023

20. Supplementary Figure 8 from Implication of Metastasis Suppressor NM23-H1 in Maintaining Adherens Junctions and Limiting the Invasive Potential of Human Cancer Cells

Author

Marie-Lise Lacombe, Christian Gespach, Philippe Chavrier, Marc Bracke, Philippe Birembaut, Béatrice Nawrocki-Raby, Sylvie Dufour, Christèle Desbois-Mouthon, Nicolas Chignard, Renaud Poincloux, Dominique Wendum, Floria Lizarraga, Olivier De Wever, and Mathieu Boissan

Abstract

Supplementary Figure 8 from Implication of Metastasis Suppressor NM23-H1 in Maintaining Adherens Junctions and Limiting the Invasive Potential of Human Cancer Cells

Published
2023

21. Intraoperative random biopsies of strictureplasty sites can detect early small-bowel adenocarcinoma in patients with Crohn's disease

Author

Chloé Martineau, Jérémie H. Lefèvre, Najim Chafai, Lauren O'Connell, Magali Svrcek, Laurent Beaugerie, Lionel Arrive, Nicolas Benech, Anne Bourrier, Marine Camus, Edouard Chambenois, Ulriikka Chaput, Clotilde Debove, Xavier Dray, Jean-François Flejou, Nadia Hoyeau, Julien Kirchgesner, Cécilia Landman, Romain Leenhardt, Jérémie H. Lefevre, Philippe Marteau, Isabelle Nion-Larmurier, Yann Parc, Philippe Seksik, Laura Sirmai, Harry Sokol, and Dominique Wendum

Subjects
medicine.medical_specialty, Crohn's disease, Hepatology, business.industry, medicine.medical_treatment, Gastroenterology, MEDLINE, Small bowel adenocarcinoma, medicine.disease, Internal medicine, Strictureplasty, Medicine, In patient, business
Published
2021

22. <scp>RIPK3</scp> dampens mitochondrial bioenergetics and lipid droplet dynamics in metabolic liver disease

Author

Marta B. Afonso, Tawhidul Islam, Julie Magusto, Ricardo Amorim, Véronique Lenoir, Rui F. Simões, José Teixeira, Liana C. Silva, Dominique Wendum, Isabelle Jéru, Corinne Vigouroux, Rui E. Castro, Paulo J. Oliveira, Carina Prip‐Buus, Vlad Ratziu, Jérémie Gautheron, Cecília M. P. Rodrigues, Prip-Buus, Carina, Universidade de Lisboa, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Coimbra [Portugal] (UC), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre de Référence des Maladies Rares - Maladies Inflammatoires des Voies Biliaires et Service d’Hépatologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre National de Référence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité [CHu Saint-Antoine] (PRISIS), CHU Saint-Antoine [AP-HP], [Institut Cochin] Département Endocrinologie, métabolisme, diabète (EMD) (EMD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)

Subjects
[SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Hepatology, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology
Abstract

International audience; Background and aims: Receptor-interacting protein kinase 3 (RIPK3) mediates NAFLD progression, but its metabolic function is unclear. Here, we aimed to investigate the role of RIPK3 in modulating mitochondria function, coupled with lipid droplet (LD) architecture in NAFLD.Approach and results: Functional studies evaluating mitochondria and LD biology were performed in wild-type (WT) and Ripk3-/- mice fed a choline-deficient, amino acid-defined (CDAA) diet for 32 and 66 weeks and in CRISPR-Cas9 Ripk3-null fat-loaded immortalized hepatocytes. The association between hepatic perilipin (PLIN) 1 and 5, RIPK3, and disease severity was also addressed in a cohort of patients with NAFLD and in PLIN1-associated familial partial lipodystrophy. Ripk3 deficiency rescued impairment in mitochondrial biogenesis, bioenergetics, and function in CDAA diet-fed mice and fat-loaded hepatocytes. Ripk3 deficiency was accompanied by a strong upregulation of antioxidant systems, leading to diminished oxidative stress upon fat loading both in vivo and in vitro. Strikingly, Ripk3-/- hepatocytes displayed smaller size LD in higher numbers than WT cells after incubation with free fatty acids. Ripk3 deficiency upregulated adipocyte and hepatic levels of LD-associated proteins PLIN1 and PLIN5. PLIN1 upregulation controlled LD structure and diminished mitochondrial stress upon free fatty acid overload in Ripk3-/- hepatocytes and was associated with diminished human NAFLD severity. Conversely, a pathogenic PLIN1 frameshift variant was associated with NAFLD and fibrosis, as well as with increased hepatic RIPK3 levels in familial partial lipodystrophy.Conclusions: Ripk3 deficiency restores mitochondria bioenergetics and impacts LD dynamics. RIPK3 inhibition is promising in ameliorating NAFLD.

Published
2022

23. Protective potential of the gallbladder in primary sclerosing cholangitis

Author

Nora Cazzagon, Ester Gonzalez-Sanchez, Haquima El-Mourabit, Dominique Wendum, Dominique Rainteau, Lydie Humbert, Christophe Corpechot, Olivier Chazouillères, Lionel Arrivé, Chantal Housset, and Sara Lemoinne

Subjects
Magnetic resonance imaging, Hepatology, Gastroenterology, Internal Medicine, Immunology and Allergy, Abcb4 knockout mice, Bile acids, Cholecystectomy, Gallbladder volume
Published
2022

24. Nestin as a diagnostic and prognostic marker for combined hepatocellular-cholangiocarcinoma

Author

Julien Calderaro, Luca Di Tommaso, Pascale Maillé, Aurélie Beaufrère, Cong Trung Nguyen, Lara Heij, Viviane Gnemmi, Rondell P. Graham, Frédéric Charlotte, Suzanne Chartier, Dominique Wendum, Mukul Vij, Daniela Allende, Alba Diaz, Carla Fuster, Benjamin Rivière, Astrid Herrero, Jérémy Augustin, Katja Evert, Diego Francesco Calvisi, Wei Qiang Leow, Howard Ho Wai Leung, Jan Bednarsch, Emmanuel Boleslawski, Mohamed Rela, Anthony Wing-Hung Chan, Alejandro Forner, Maria Reig, Anaïs Pujals, Loetitia Favre, Manon Allaire, Olivier Scatton, Arnaud Uguen, Eric Trépo, Lukas Otero Sanchez, Denis Chatelain, Myriam Remmelink, Camille Boulagnon-Rombi, Céline Bazille, Nathalie Sturm, Benjamin Menahem, Eric Frouin, David Tougeron, Christophe Tournigand, Emmanuelle Kempf, Haeryoung Kim, Massih Ningarhari, Sophie Michalak-Provost, Jakob Nikolas Kather, Annette S.H. Gouw, Purva Gopal, Raffaele Brustia, Eric Vibert, Kornelius Schulze, Darius F. Rüther, Sören A. Weidemann, Rami Rhaiem, Jean-Charles Nault, Alexis Laurent, Giuliana Amaddeo, Hélène Regnault, Eleonora de Martin, Christine Sempoux, Pooja Navale, Jayendra Shinde, Ketan Bacchuwar, Maria Westerhoff, Regina Cheuk-Lam Lo, Mylène Sebbagh, Catherine Guettier, Marie Lequoy, Mina Komuta, Marianne Ziol, Valérie Paradis, Jeanne Shen, Stefano Caruso, Hôpital Henri Mondor, Istituto Clinico Humanitas [Milan] (IRCCS Milan), Humanitas University [Milan] (Hunimed), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de Pathologie [Hôpital Beaujon - APHP], Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Molecular virology and immunology – Physiopathology and therapeutic of chronic viral hepatitis (Team 18) (Inserm U955), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), CHU Lille, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Thérapies Laser Assistées par l'Image pour l'Oncologie - U 1189 (ONCO-THAI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Henri Mondor [Créteil], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Université libre de Bruxelles (ULB), CHirurgie, IMagerie et REgénération tissulaire de l’extrémité céphalique - Caractérisation morphologique et fonctionnelle - UR UPJV 7516 (CHIMERE), Université de Picardie Jules Verne (UPJV), Laboratoire de Signalisation et Récepteurs Matriciels (SiRMa), Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Département de Pathologie [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Grenoble, Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Chirurgie Viscérale et Digestive [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé (LIMICS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, Groupe Henri Mondor-Albert Chenevier, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Johns Hopkins University (JHU), Hôpital Claude Huriez [Lille], Physiopathologie et traitement des maladies du foie, Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Centre Hospitalier Universitaire de Reims (CHU Reims), Génomique fonctionnelle des tumeurs solides = Functional Genomics of Solid Tumors [CRC] (FunGeST), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Labex OncoImmunology, Equipe labellisée Ligue Contre le Cancer, Université Paris Descartes - Paris 5 (UPD5), Service d'Hépatologie [Avicenne], Hôpital Avicenne [AP-HP], Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine [Bobigny], Université Paris 13 (UP13)-Sorbonne Paris Cité, Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Crosscope, University of Michigan [Ann Arbor], University of Michigan System, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Hôpital Bicêtre, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d’Anatomie Pathologique [CHU Beaujon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], Labex Immuno-oncology [Paris] ( Université Paris Descartes - Paris 5 - PRES Sorbonne Paris Cité), Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité, Service d'Anatomie et cytologie pathologiques [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Anatomie et cytologie pathologiques = Service de Pathologie [CHU Pitié-Salpêtrière] (ACP), CHU Henri Mondor, Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École pratique des hautes études (EPHE), Service d'Hépato-gastro-entérologie [CHU Saint-Antoine], and Groningen Institute for Organ Transplantation (GIOT)

Subjects
Carcinoma, Hepatocellular, Hepatology, combined hepatocellular-cholangiocarcinoma, Liver Neoplasms, hepatocellular carcinoma, liver, Prognosis, Nestin, Cholangiocarcinoma, Bile Ducts, Intrahepatic, Bile Duct Neoplasms, cancer, Humans, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Background & Aims: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer (PLC) associated with a poor prognosis. Given the challenges in its identification and its clinical implications, biomarkers are critically needed. We aimed to investigate the diagnostic and prognostic value of the immunohistochemical expression of Nestin, a progenitor cell marker, in a large multicentric series of PLCs.Methods: We collected 461 cHCC-CCA samples from 32 different clinical centers. Control cases included 368 hepatocellular carcinomas (HCCs) and 221 intrahepatic cholangiocarcinomas (iCCAs). Nestin immunohistochemistry was performed on whole tumor sections. Diagnostic and prognostic performances of Nestin expression were determined using receiver-operating characteristic curves and Cox regression modeling.Results: Nestin was able to distinguish cHCC-CCA from HCC with AUCs of 0.85 and 0.86 on surgical and biopsy samples, respectively. Performance was lower for the distinction of cHCC-CCA from iCCA (AUCs of 0.59 and 0.60). Nestin, however, showed a high prognostic value, allowing identification of the subset of cHCC-CCA (“Nestin High”, >30% neoplastic cells with positive staining) associated with the worst clinical outcome (shorter disease-free and overall survival) after surgical resection and liver transplantation, as well as when assessment was performed on biopsies.Conclusion: We show in different clinical settings that Nestin has diagnostic value and that it is a useful biomarker to identify the subset of cHCC-CCA associated with the worst clinical outcome. Nestin immunohistochemistry may be used to refine risk stratification and improve treatment allocation for patients with this highly aggressive malignancy. Lay summary: There are different types of primary liver cancers (i.e. cancers that originate in the liver). Accurately identifying a specific subtype of primary liver cancer (and determining its associated prognosis) is important as it can have a major impact on treatment allocation. Herein, we show that a protein called Nestin could be used to refine risk stratification and improve treatment allocation for patients with combined hepatocellular carcinoma, a rare but highly aggressive subtype of primary liver cancer.

Published
2021

25. A systemic mechanism of increased transendothelial migration of leukocytes through the blood-brain barrier in hepatic encephalopathy

Author

Pierre-Olivier Couraud, Dominique Wendum, Martin Journaux, Nicolas Weiss, Haquima El Mourabit, Augustin Schaeffer, E. Lasnier, Marika Rudler, Chantal Housset, Dominique Thabut, and S. Mouri

Subjects
Liver Cirrhosis, Pathology, medicine.medical_specialty, Cirrhosis, Blood–brain barrier, Systemic inflammation, Leukocytes, Medicine, Humans, Hepatic encephalopathy, Inflammation, Hepatology, U937 cell, business.industry, Gastroenterology, Transendothelial and Transepithelial Migration, Hyperammonemia, U937 Cells, medicine.disease, In vitro, Pathophysiology, medicine.anatomical_structure, Blood-Brain Barrier, Hepatic Encephalopathy, medicine.symptom, business
Abstract

Background Hepatic encephalopathy (HE) is a frequent neurological complication of cirrhosis. Evidence suggests a synergic pathophysiological implication of hyperammonemia and systemic inflammation. In addition, the blood-brain barrier (BBB) permeability can be impaired in cirrhotic patients, notably in those displaying HE. We hypothesized that systemic inflammation could trigger leukocytes transendothelial migration (TEM) through the BBB in cirrhotic patients and especially those with HE. Methods We studied the effects of patients’ plasma on the TEM of the leukocyte U937 cell line in vitro, using a validated BBB model (hCMEC/D3 cell line). We compared TEM of U937 leukocytes across hCMEC/D3 monolayer incubated with the plasma of i) patients with cirrhosis without HE, ii) patients with cirrhosis and HE, iii) healthy controls. Results We show that the plasma of cirrhotic patients with HE enhances TEM of U937 leukocytes across hCMEC/D3 BBB model. We found a correlation between U937 TEM on the one hand, the West-Haven score and ammonemia on the other one. A trend towards a correlation between U937 TEM and PS-100Beta in plasma, a marker of BBB solute's permeability increase, was also found. Conclusion These findings suggest that circulating factors could increase leukocytes TEM in cirrhotic patients and contribute to the increased BBB permeability that has been described in cirrhotic patients with HE.

Published
2021

26. ATP-binding cassette transporters expression in rats with cirrhosis and hepatic encephalopathy

Author

Haquima El Mourabit, Chantal Housset, Nicolas Weiss, Charlotte Bouzbib, S. Mouri, Dominique Thabut, Marika Rudler, E. Lasnier, and Dominique Wendum

Subjects
Liver Cirrhosis, Cirrhosis, Hepatology, business.industry, Multidrug resistance-associated protein 2, Encephalopathy, Gastroenterology, Inflammation, ATP-binding cassette transporter, Pharmacology, medicine.disease, Chronic liver disease, Pathophysiology, Rats, Neoplasm Proteins, Hepatic Encephalopathy, medicine, Animals, ATP Binding Cassette Transporter, Subfamily G, Member 2, ATP-Binding Cassette Transporters, medicine.symptom, Multidrug Resistance-Associated Proteins, business, Hepatic encephalopathy
Abstract

Background Pathophysiology of acute encephalopathy in cirrhotic patients is not completely understood. Factors implicated include ammonia, inflammation, various metabolic disorders and drug toxicity. Recent studies have evidenced an increased permeability of the blood-brain barrier (BBB) in models of chronic liver disease and encephalopathy, either to solutes, or to leukocytes. A modification of the expression of BBB ATP-Binding Cassette (ABC) transporters, actively transporting endogenous and exogenous components through the BBB, has been described in models of acute liver failure. We hypothesized that a modification of ABC transporters expression may contribute to drug-induced acute encephalopathy in cirrhosis. Materiel and methods A rat model of cirrhosis induced by Bile Duct Ligation (BDL) was studied, and compared to a SHAM rat model. Rats were sacrificed and brains studied after decapitation. Genic expression of ABC transporters, including P-gp, BCRP, MRP1, MRP2, MRP4 and MRP5 was evaluated by RT-qPCR on isolated brain microvessels. Encephalopathy was assessed 6 weeks after surgery by a trail suspension test and an Open Field Test. Results BDL rats developed a histologically proven cirrhosis and displayed a higher ammonemia than SHAM rats (183 µmol/L vs 53 µmol/L, p=0.0003). BDL rats presented with encephalopathy shown by neurobehavioral tests. MRP2 was not detected neither in BDL nor in SHAM rats. There was a decrease in the genic expression of MRP5 6 weeks after surgery. Expressions of P-gp, BCRP, MRP1 and MRP4 were not different between the 2 groups. Conclusion We suggest that acute encephalopathy in cirrhotic BDL rats may be associated to a modification of ABC transporter MRP5 on the BBB, that could be responsible for a decrease clearance of neurotoxic agents.

Published
2021

27. Hypercalcemia and Acute Renal Failure Indicating Peritoneal Sarcoidosis

Author

Mathieu Gauthé, Claude Bachmeyer, Jean Philippe Haymann, Valeria Loi, Nicolas Belaube, and Dominique Wendum

Subjects
medicine.medical_specialty, business.industry, Internal medicine, medicine, General Medicine, Sarcoidosis, medicine.disease, business, Gastroenterology
Published
2021

28. Diet‐Induced Dysbiosis and Genetic Background Synergize With Cystic Fibrosis Transmembrane Conductance Regulator Deficiency to Promote Cholangiopathy in Mice

Author

Ivan Moszer, Dominique Wendum, Haquima El Mourabit, Dominique Rainteau, Yves Chrétien, Fatiha Merabtene, Harry Sokol, Chantal Housset, Damien Ulveling, Loic Brot, and Dominique Debray

Subjects
0301 basic medicine, medicine.medical_specialty, medicine.drug_class, Gut flora, Cystic fibrosis, 03 medical and health sciences, Liver disease, 0302 clinical medicine, Internal medicine, medicine, lcsh:RC799-869, Intestinal permeability, Hepatology, Bile acid, biology, Fatty liver, Original Articles, medicine.disease, biology.organism_classification, Cystic fibrosis transmembrane conductance regulator, 030104 developmental biology, Endocrinology, biology.protein, 030211 gastroenterology & hepatology, Original Article, lcsh:Diseases of the digestive system. Gastroenterology, Dysbiosis
Abstract

The most typical expression of cystic fibrosis (CF)-related liver disease is a cholangiopathy that can progress to cirrhosis. We aimed to determine the potential impact of environmental and genetic factors on the development of CF-related cholangiopathy in mice. Cystic fibrosis transmembrane conductance regulator (Cftr)-/- mice and Cftr +/+ littermates in a congenic C57BL/6J background were fed a high medium-chain triglyceride (MCT) diet. Liver histopathology, fecal microbiota, intestinal inflammation and barrier function, bile acid homeostasis, and liver transcriptome were analyzed in 3-month-old males. Subsequently, MCT diet was changed for chow with polyethylene glycol (PEG) and the genetic background for a mixed C57BL/6J;129/Ola background (resulting from three backcrosses), to test their effect on phenotype. C57BL/6J Cftr -/- mice on an MCT diet developed cholangiopathy features that were associated with dysbiosis, primarily Escherichia coli enrichment, and low-grade intestinal inflammation. Compared with Cftr +/+ littermates, they displayed increased intestinal permeability and a lack of secondary bile acids together with a low expression of ileal bile acid transporters. Dietary-induced (chow with PEG) changes in gut microbiota composition largely prevented the development of cholangiopathy in Cftr -/- mice. Regardless of Cftr status, mice in a mixed C57BL/6J;129/Ola background developed fatty liver under an MCT diet. The Cftr -/- mice in the mixed background showed no cholangiopathy, which was not explained by a difference in gut microbiota or intestinal permeability, compared with congenic mice. Transcriptomic analysis of the liver revealed differential expression, notably of immune-related genes, in mice of the congenic versus mixed background. In conclusion, our findings suggest that CFTR deficiency causes abnormal intestinal permeability, which, combined with diet-induced dysbiosis and immune-related genetic susceptibility, promotes CF-related cholangiopathy.

Published
2018

29. Dissociation of humoral and cellular immune responses in kidney transplant recipients with EBV mucocutaneous ulcer

Author

Dominique Wendum, Thierry Jo Molina, Christophe Legendre, Julien Rossignol, Olivier Hermine, Rebecca Sberro-Soussan, Pierre Isnard, Julie Bruneau, and Lucienne Chatenoud

Subjects
Transplantation, biology, business.industry, Mucocutaneous zone, 030230 surgery, medicine.disease, medicine.disease_cause, Epstein–Barr virus, Post-transplant lymphoproliferative disorder, Pathophysiology, 03 medical and health sciences, 0302 clinical medicine, Infectious Diseases, Immune system, hemic and lymphatic diseases, Immunology, medicine, biology.protein, 030211 gastroenterology & hepatology, Stem cell, Antibody, business
Abstract

EBV-positive mucocutaneous ulcer (EBV-MCU) is a rare EBV-positive B-cell lymphoproliferative disorder occurring in immunocompromised patients such as patients with solid organ or hematopoietic stem cells transplantation. EBV-MCU often consists of an isolated and circumscribed cutaneous or mucosal ulcerative lesion with a self-limited growth potential and a high regression rate upon immunosuppressive treatment withdrawal or rituximab therapy. Nevertheless, the pathophysiology of this latent infection leading to clonal lymphoproliferation is not well established. We report here two cases of EBV-MCU in kidney transplant recipients with a dissociated immune response to EBV with the absence of EBV-related antibodies and a positive T-cell response to EBV suggesting a potential specific oncogenic mechanism in this lymphoproliferative disorder.

Published
2021

30. Cholangiopathy aggravation is caused by VDR ablation and alleviated by VDR-independent vitamin D signaling in ABCB4 knockout mice

Author

Marie Clavel, Haquima El Mourabit, Marion Jager, Sophie Moog, Ester Gonzalez-Sanchez, Jérémie Gautheron, Tatiana Ledent, Chantal Housset, Laura Fouassier, Dominique Wendum, Axelle Cadoret, Javier Vaquero, and Nicolas Chignard

Subjects
0301 basic medicine, Vitamin, Male, ATP Binding Cassette Transporter, Subfamily B, Calcitriol receptor, Cholangiocyte, Proinflammatory cytokine, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Vitamin D and neurology, Medicine, Animals, Vitamin D, Molecular Biology, Mice, Knockout, Cholestasis, business.industry, Vitamins, Fibrosis, Mice, Inbred C57BL, 030104 developmental biology, chemistry, Knockout mouse, Cancer research, Molecular Medicine, Receptors, Calcitriol, 030211 gastroenterology & hepatology, Tumor necrosis factor alpha, Signal transduction, business, Gene Deletion, Signal Transduction
Abstract

Background & aims Cholangiopathies are chronic liver diseases in which damaged cholangiocytes trigger a proinflammatory and profibrotic reaction. The nuclear vitamin D receptor (VDR) is highly expressed in cholangiocytes and exerts immune-regulatory functions in these cells. In the present study, we examined the protective function of VDR and other vitamin D signaling pathways in chronic cholangiopathy and cholangiocytes. Methods Vdr was invalidated in Abcb4 knockout mice, a widely used animal model of chronic cholangiopathy. The impact of vitamin D signaling on cholangiopathy features was examined in vivo and in cholangiocytes (primary and cell lines). Results Cholangiopathy features (i.e, cholestasis, ductular reaction and fibrosis) were aggravated in Vdr;Abcb4 double knockout mice compared to the Abcb4 simple knockout, and associated with an overexpression of proinflammatory factors. The proinflammatory phenotype of cholangiocytes was also exacerbated following VDR silencing in vitro. The expression of proinflammatory factors and the severity of cholangiopathy were reduced in the double knockout mice treated with the vitamin D analog calcipotriol or with vitamin D. In vitro, the inflammatory response to TNFα was significantly reduced by calcipotriol in biliary cells silenced for VDR, and this effect was abolished by co-silencing the plasma membrane receptor of vitamin D, protein disulfide-isomerase A3 (PDIA3). Conclusions Our results demonstrate an anti-inflammatory role of VDR signaling in cholangiocytes and cholangiopathy. They also provide evidence for PDIA3-mediated anti-inflammatory effects of vitamin D and vitamin D analog in these settings.

Published
2020

31. Cannabis Use and Plasma Human Immunodeficiency Virus (HIV) RNA Levels in Patients Coinfected With HIV and Hepatitis C Virus Receiving Antiretroviral Therapy: Data From the ANRS CO13 HEPAVIH Cohort

Author

M Chalouni, D Vittecocq, C Rouzaud, C Gilbert, P Bellecave, H Stitou, Thoirain-Galvan, F Touam, C Debreux, D Croisier-Bertin, S Gillet, A de Monte, Patrick Miailhes, F Valour, M L Batard, Lionel Piroth, Joseph Koffi, Y Baazia, Dominique Salmon-Ceron, Morane Cavellec, Gilles Peytavin, B Spire, H Dutronc, C Partouche, Lawrence Serfaty, M Brollo, G Melica, P Catalan, Pascale Trimoulet, P Fischer, David Boutoille, A Mélard, M Mora, P Callard, C Tumiotto, Marianne Maynard, P Bertheau, L Lacaze-Buzy, M Nishimwe, T Pistone, S Fourati, F Roustant, Fabienne Marcellin, Chambrin, S Galim, J Haudebourg, L Traore, S Dominguez, Claudine Duvivier, Brodard, C Rivoisy, M Pauchard, H Laroche, C Katlama, C Allavena, Jean-Daniel Lelièvre, S Fafi-Kremer, K. Barange, S Anriamiandrisoa, D Lacoste, M Desvallees, Karine Lacombe, Marianne Ziol, P Duffau, M Baudoin, Laurent Alric, Y Lévy, Laurent Cotte, Athenaïs Gerber, Rio, P Fisher, C Deback, P Thilbaut, C Louisin, P Platterier, F. Boufassa, Jacques Izopet, S Tezkratt, Reliquet, Philippe Lack, Yazdan Yazdanpanah, Olivier Lortholary, C Pallier, Isabelle Poizot-Martin, S Caldato, Pierre-Marie Girard, A Joulie, P Tremeaux, F Bendjaballah, Julie Chas, François Bailly, J Krause, J Polo Devoto, N Hall, J F Paccalin, Eric Billaud, Yves Benhamou, E Bedel, D. Neau, Tangui Barré, S Gohier, A. Bicart-See, David Zucman, S. Radenne, A S Lascaux, S Ogoudjobi, M L Chaix, C Majerholc, D Malvy, B Marchou, S Reigadas, F Biron, Brigitte Autran, Amaury Martin, C Greib, J Lourenco, Félix Bonnet, E Blanchard, S Bouchez, J Selves, F Dauchy, C Viala, Tristan Ferry, M Partisani, F Marcellin, D. Zucman, D Lambert, Y Ousidhoum, F Z Makhoukhi, P Roux, I Faure, Firouzé Bani-Sadr, Vincent Di Beo, C Le Pendeven, C Protopopescu, M Hentzien, M Le Cam, C Pignon, M Mebarki, A-S Ritleg, M Vandenhende, Hélène Fontaine, Philippe Morlat, C Martins, Marc-Antoine Valantin, Iwaka-Bande, André Boibieux, S Castet-Lafarie, A. Naqvi, Patrice Cacoub, L. Wittkop, A Rodallec, H. Aumaitre, Melina Erica Santos, Dominique Wendum, Petrov-Sanchez, Linda Wittkop, L Berroukeche, I Kansau, D Beniken, Constance Delaugerre, E Farfour, Philippe Sogni, M Buisson, Majid Amiri, François Raffi, David Rey, A Salmon Rousseau, Patrick Mercié, L Le Guen, C Cazanave, Pascal Chavanet, M Santos, Conte, S Akel, P Mercié, E de Mautort, L Chalal, Avettand-Fenoel, Caroline Scholtes, J Zelie, S Nafissa, J F Viallard, D. Lebrasseur-Longuet, Di Beo, Y Nguyen, A Soria, J Adam, C Biron, B Terris, Sarah Maylin, M Favier, Jean-Michel Molina, T Lemboub, Giordanengo, I Kmiec, C. Solas, L Michel, F Charlotte, A.M. Roque, M Hessamfar, C Augustin-Normand, Cécile Goujard, J L Berger, S Breau, H Hue, Sicart-Payssan, J L Pellegrin, P Cervera, A Desclaux, R Bayoud, A. Simon, M Uzan, M Priester, C Cheneau, Caroline Lascoux-Combe, C Chesnel, S Abgrall, M Duong Van Huyen, N Bernard, D Garipuy, E Gardiennet, D Peyramond, D Bornarel, Michel Dupon, F Larroquette, O Zaegel, P Gantner, C Lions, A Waldner-Combernoux, P Miailhes, A Ivanova, Christian Chidiac, Fabien Zoulim, M Mole, R Ben Rayana, H Adle-Biassette, François Nicot, L Esterle, L Meyer, Martinez, F Ader, A Adda-Lievin, P Carrieri, A. Gervais, C Martell, S Mahy, E Lazzaro, P Sogni, T Barré, R Knight, M C Pertusa, J. Bottero, Patrizia Carrieri, T Perpoint, Olivier Bouchaud, D Costagliola, C Gatey, E. Rosenthal, Dominique Salmon, S Lepuil, L Dequae-Merchadou, E Teicher, S Parlier, C Bolliot, G Alexandre, Sophie Metivier, O Braik, M C Receveur, Corinne Brochier, C Hemon, R Usubillaga, François Boué, M Méchain, Camelia Protopopescu, A Ochoa, Catherine Tamalet, M J Ferro-Collados, M P Pietri, P Bioulac-Sage, M C Saint-Paul, T T Le-Thi, M Lefebvre, Paradis, Le Baut, Chloe Pomes, Y Quertainmont, C Bernard-Henry, C Amiel, Gilles Pialoux, R Fior, Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Observatoire régional de la santé Provence-Alpes-Côte d'Azur [Marseille] (ORS PACA), Service des maladies infectieuses et tropicales [CH Lyon Sud - HCL] (Hôpital de la Croix-Rousse), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL), Service de médecine interne et maladies infectieuses [Bordeaux], CHU Bordeaux [Bordeaux]-Groupe hospitalier Saint-André, Service Maladies infectieuses et tropicales [AP-HP Hôpital Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), Institut de Santé Publique, d'Epidémiologie et de Développement (ISPED), Université Bordeaux Segalen - Bordeaux 2, Team MORPH3EUS (INSERM U1219 - UB - ISPED), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC Bordeaux, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Médecine Interne [Hôpital Foch, Suresnes] (SMI), Hôpital Foch [Suresnes], Département d'hépatologie [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunité Innée - Innate Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Dupuis, Christine, INSERM U1197, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]

Subjects
Microbiology (medical), Hepatitis C virus, [SDV]Life Sciences [q-bio], Human immunodeficiency virus (HIV), 030508 substance abuse, HIV Infections, Hepacivirus, medicine.disease_cause, 03 medical and health sciences, Plasma, 0302 clinical medicine, medicine, Humans, In patient, 030212 general & internal medicine, ComputingMilieux_MISCELLANEOUS, Cannabis, business.industry, Coinfection, HIV, Cannabis use, Hepatitis C, Chronic, Virology, Antiretroviral therapy, Hepatitis C, 3. Good health, [SDV] Life Sciences [q-bio], Infectious Diseases, Cohort, RNA, 0305 other medical science, business
Abstract

International audience; No abstract available

Published
2020

32. Testing for ROS1, ALK, MET, and HER2 rearrangements and amplifications in a large series of biliary tract adenocarcinomas

Author

Dominique Wendum, Françoise Praz, Claire Calmel, Aurelie Scriva, François Paye, Pascale Cervera, Caroline Gabignon, Olivier Scatton, Jérémy Augustin, Jean-François Fléjou, Laëtitia Menu, Service d'anatomie et cytologie pathologiques [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CEREST-TC [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Service de chirurgie générale et digestive [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS), Service d'Anatomie et cytologie pathologiques [CHU Pitié-Salpêtrière] (ACP), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Service d'Anatomopathologie [CHU Saint-Antoine], Service d'Anatomie et cytologie pathologiques [CHU Saint-Antoine], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Gestionnaire, Hal Sorbonne Université

Subjects
0301 basic medicine, Pathology, Lung Neoplasms, Receptor, ErbB-2, Aneuploidy, Chromosomal translocation, 0302 clinical medicine, Chromosome instability, Anaplastic Lymphoma Kinase, Biliary Tract, In Situ Hybridization, Fluorescence, ComputingMilieux_MISCELLANEOUS, Gene Rearrangement, Bile duct, General Medicine, Protein-Tyrosine Kinases, Proto-Oncogene Proteins c-met, Immunohistochemistry, 3. Good health, medicine.anatomical_structure, Biliary tract, 030220 oncology & carcinogenesis, MET, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], ROS1, medicine.medical_specialty, Adenocarcinoma of Lung, [SDV.CAN]Life Sciences [q-bio]/Cancer, Adenocarcinoma, Fluorescent in situ hybridization, Pathology and Forensic Medicine, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Biliary tract adenocarcinoma, Proto-Oncogene Proteins, HER2, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Humans, Molecular Biology, business.industry, Gallbladder, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Cell Biology, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 030104 developmental biology, business
Abstract

International audience; Biliary tract carcinomas are divided into intrahepatic, perihilar, distal extrahepatic cholangiocarcinomas, and gallbladder adenocarcinomas. Therapies targeting ROS1, ALK, MET, and HER2 alterations are currently evaluated in clinical trials. We assessed ROS1 and ALK translocations/amplifications as well as MET and HER2 amplifications for each tumor subtype by fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC) in 73 intrahepatic, 40 perihilar bile duct, 36 distal extrahepatic cholangiocarcinomas, and 45 gallbladder adenocarcinomas (n = 194). By FISH, we detected targetable alterations in 5.2% of cases (n = 10): HER2 and MET amplifications were found in 4.1% (n = 8) and 1.0% (n = 2), respectively. The HER2-amplified cases were mostly gallbladder adenocarcinomas (n = 5). The MET- and HER2-amplified cases were all positive by IHC. Fourteen cases without MET amplification were positive by IHC, whereas HER2 over-expression was detected by IHC only in HER2-amplified cases. We detected no ALK or ROS1 translocation or amplification. Several alterations were consistent with aneuploidy: 24 cases showed only one copy of ROS1 gene, 4 cases displayed a profile of chromosomal instability, and an over-representation of centromeric alpha-satellite sequences was found in five cases. We confirm a relatively high rate of HER2 amplifications in gallbladder adenocarcinomas and the efficacy of IHC to screen these cases. Our results also suggest the value of IHC to screen MET amplification. Contrary to initial publications, ROS1 rearrangements seem to be very rare in biliary tract adenocarcinomas. We confirm a relatively high frequency of aneuploidy and chromosomal instability and reveal the over-representation of centromeric alpha-satellite sequences in intrahepatic cholangiocarcinomas.

Published
2020

33. Chronic Hepatitis E Viral Infection After Liver Transplantation

Author

Alessandra Mazzola, Dominique Wendum, Margherita Tran Minh, Yvon Calmus, Filomena Conti, Frédéric Charlotte, Aisha Hdiji, and Denis Bernard

Subjects
medicine.medical_specialty, Alcoholic liver disease, Cirrhosis, viruses, medicine.medical_treatment, Liver transplantation, Gastroenterology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Medicine, 030212 general & internal medicine, Hepatitis, Transplantation, business.industry, Ribavirin, virus diseases, medicine.disease, digestive system diseases, Chronic infection, chemistry, 030211 gastroenterology & hepatology, Liver function, business, Viral load
Abstract

Hepatitis E virus (HEV) infection is increasingly being reported in immunocompromised patients and particularly organ transplant recipients. In this context, HEV infection frequently evolves to chronic infection with a rapid progression of fibrosis to cirrhosis. Ribavirin monotherapy and a minimization of immunosuppression represent the treatment of choice, with a good response rate. However, no data are available on whether treatment can achieve a regression of liver fibrosis in chronic HEV patients. A 57-year-old male patient received a liver transplant for alcoholic cirrhosis and, 6 years later, developed biopsy-proven chronic HEV infection. The patient received different antiviral therapy regimens (pegylated interferon alpha 2b and ribavirin different dosages, and long-term treatment with ribavirin monotherapy still ongoing) but without achieving a sustained virological response. Liver function parameters normalized after 1 month of treatment but without the clearance of HEV. Hepatitis E virus RNA levels also remained detectable in the serum and stools throughout ribavirin monotherapy. No serious adverse events were reported. A gradual regression of liver fibrosis was reported (Metavir A0/F1 in 2015 versus A3/F4 in 2008). Long-term treatment with ribavirin is safe in liver transplant recipients, without achieving HEV sustained virological response, and may induce a biopsy-proven regression of liver fibrosis in a liver transplant recipient with cirrhosis after chronic HEV infection.

Published
2017

34. Temporal trends, clinical patterns and outcomes of NAFLD-related HCC in patients undergoing liver resection over a 20-year period

Author

Dominique Wendum, V. Ratziu, Olivier Rosmorduc, Laetitia Fartoux, Olivier Scatton, Claire Goumard, and Raluca Pais

Subjects
Liver Cirrhosis, Male, medicine.medical_specialty, Carcinoma, Hepatocellular, Cirrhosis, Chronic liver disease, Gastroenterology, Article, 03 medical and health sciences, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Risk Factors, Fibrosis, Internal medicine, Diabetes mellitus, Prevalence, medicine, Hepatectomy, Humans, Pharmacology (medical), Aged, Hepatitis, Hepatology, business.industry, Liver Neoplasms, Fatty liver, Middle Aged, medicine.disease, Hepatitis C, digestive system diseases, Liver, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Etiology, Female, 030211 gastroenterology & hepatology, Neoplasm Recurrence, Local, business
Abstract

SummaryBackground Non-alcoholic fatty liver disease (NAFLD) is an increasing cause of hepatocellular carcinoma (HCC) worldwide. NAFLD-HCC often occurs in noncirrhotic liver raising important surveillance issues. Aim To determine the temporal trends for prevalence, clinical characteristics and outcomes of NAFLD-HCC in patients undergoing liver resection. Methods Consecutive patients with histologically confirmed HCC who underwent liver resection over a 20-year period (1995-2014). NAFLD was diagnosed based on past or present exposure to obesity or diabetes without other causes of chronic liver disease. Results A total of 323 HCC patients were included, 12% with NAFLD. From 1995-1999 to 2010-2014, the prevalence of NAFLD-HCC increased from 2.6% to 19.5%, respectively, P = .003, and followed the temporal trends in the prevalence of metabolic risk factors (28% vs 52%, P = .017), while hepatitis C-HCC decreased (from 43.6% to 19.5%, P = .003). NAFLD-HCC occurred more frequently in the absence of bridging fibrosis/cirrhosis (63% of cases, P

Published
2017

35. Insulin receptor isoform A favors tumor progression in human hepatocellular carcinoma by increasing stem/progenitor cell features

Author

Dominique Wendum, Olivier Scatton, Marie Lequoy, Christèle Desbois-Mouthon, Olivier Rosmorduc, Laura Fouassier, Fatiha Merabtene, Zeina Salamé, Yves Chrétien, Laetitia Fartoux, Eva Benabou, Françoise Praz, Sylvana Tahraoui, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU), Service de Pathologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université, Service d'hépatologie [Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Unité Mixte de Service d'Imagerie et de Cytométrie (UMS LUMIC), Service d'hépatologie [CHU Saint-Antoine], Service de Chirurgie Digestive, Hépato-Bilio-pancréatique et Transplantation Hépatique [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Gestionnaire, Hal Sorbonne Université, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Service d'Hépato-gastro-entérologie [CHU Saint-Antoine]

Subjects
0301 basic medicine, Cancer Research, Carcinoma, Hepatocellular, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, Mice, SCID, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, 03 medical and health sciences, Mice, 0302 clinical medicine, Downregulation and upregulation, [SDV.CAN] Life Sciences [q-bio]/Cancer, Invasion, Antigens, CD, Mice, Inbred NOD, Cell Line, Tumor, medicine, Animals, Humans, Protein Isoforms, Progenitor cell, Autocrine signalling, ComputingMilieux_MISCELLANEOUS, Liver Neoplasms, Cell migration, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Cytokeratin-19, medicine.disease, Immunohistochemistry, Receptor, Insulin, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, digestive system diseases, 3. Good health, Insulin receptor, 030104 developmental biology, Oncology, Cell culture, Tumor progression, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Cancer research, biology.protein, Disease Progression, Neoplastic Stem Cells, Heterografts, Female, INSR, Liver cancer
Abstract

International audience; Hepatocellular carcinoma (HCC) is one of the most common and deadly neoplasms. Insulin receptor (IR) exists in two isoforms, IR-A and IR-B, the latter being predominantly expressed in normal adult hepatocytes while IR-A is overexpressed in HCC to the detriment of IR-B. This study evaluated the biological functions associated with IR-A overexpression in HCC in relation to expression of its ligand IGF-II. The value of INSRA:INSRB ratio which was increased in ˜70% of 85 HCC was associated with stem/progenitor cell features such as cytokeratin-19 and α-fetoprotein and correlated with shorter patient survival. IGF2 mRNA upregulation was observed in 9.4% of HCC and was not associated with higher INSRA:INSRB ratios. Ectopic overexpression of IR-A in two HCC cell lines presenting a strong autocrine IGF-II secretion loop or not stimulated cell migration and invasion. In cells cultured as spheroids, IR-A overexpression promoted gene programs related to stemness, inflammation and cell movement. IR-A also increased cell line tumorigenicity in vivo after injection to immunosuppressed mice and the sphere-forming cells made a significant contribution to this effect. Altogether, these results demonstrate that IR-A is a novel player in HCC progression.

Published
2019

36. Preclinical Evaluation of

Author

Aurélie, Prignon, Claire, Provost, Faisal, Alshoukr, Dominique, Wendum, Anne, Couvelard, Jacques, Barbet, Patricia, Forgez, Jean-Noël, Talbot, and Anne, Gruaz-Guyon

Subjects
Diagnostic Imaging, Male, Pancreatic Neoplasms, Mice, Positron-Emission Tomography, Animals, Humans, Gallium Radioisotopes, Carcinoma, Pancreatic Ductal
Abstract

Neurotensin receptor 1 (NTSR1) is overexpressed in human pancreatic ductal adenocarcinoma (PDAC). Specific noninvasive positron-emission tomography (PET) imaging probes may improve the diagnostic accuracy and the monitoring of therapy for patients with PDAC. Here, we report the use of the

Published
2019

37. Preclinical Evaluation of 68Ga-DOTA-NT-20.3: A Promising PET Imaging Probe To Discriminate Human Pancreatic Ductal Adenocarcinoma from Pancreatitis

Author

Aurélie Prignon, Jacques Barbet, Patricia Forgez, Faisal Alshoukr, Jean-Noël Talbot, A. Gruaz-Guyon, Anne Couvelard, Dominique Wendum, Claire Provost, Laboratoire d'Imagerie Moléculaire Positonique - IFR 65 (LIMP), Sorbonne Université (SU), and Phénotypage du petit animal (UMS28)

Subjects
Biodistribution, Pathology, medicine.medical_specialty, neurotensin receptor, Neurotensin receptor 1, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Pharmaceutical Science, [SDV.CAN]Life Sciences [q-bio]/Cancer, 02 engineering and technology, [SDV.IB.MN]Life Sciences [q-bio]/Bioengineering/Nuclear medicine, 030226 pharmacology & pharmacy, 03 medical and health sciences, 0302 clinical medicine, In vivo, gallium-68, Drug Discovery, medicine, Neurotensin receptor, Tissue microarray, business.industry, Histology, 021001 nanoscience & nanotechnology, medicine.disease, 3. Good health, Molecular Medicine, Pancreatitis, positron emission tomography (PET) imaging, [SDV.IB]Life Sciences [q-bio]/Bioengineering, 0210 nano-technology, business, Ex vivo
Abstract

International audience; Neurotensin receptor 1 (NTSR1) is overexpressed in human pancreatic ductal adenocarcinoma (PDAC). Specific noninvasive positron-emission tomography (PET) imaging probes may improve the diagnostic accuracy and the monitoring of therapy for patients with PDAC. Here, we report the use of the 68 Ga-labeled neurotensin (NTS) analogue DOTA-NT-20.3 to image human PDAC in animal models and to discriminate tumors from pancreatitis. In addition to the preclinical study, two tissue microarray slides, constructed by small core biopsies (2−5) from standard paraffin-embedded tumor tissues, were used to confirm the high (78%) positivity rate of NTSR1 expression in human PDAC. PET imaging, biodistribution, blocking, and histology studies were performed in subcutaneous AsPC-1 pancreatic tumor-bearing mice. 68 Ga-DOTA-NT-20.3 PET images showed rapid tumor uptake and high contrast between the tumor and background with a fast blood clearance and a moderate accumulation in the kidneys. Ex vivo biodistribution showed low uptake in normal pancreas (0.22% IA/g) and in the remaining organs at 1 h postinjection, kidney retention (5.38 ± 0.54% IA/g), and fast clearance from blood and confirmed high uptake in tumors (5.28 ± 0.93% IA/g), leading to a tumor-to-blood ratio value of 6 at 1 h postinjection. The significant decrease of tumor uptake in a blocking study demonstrated the specificity of 68 Ga-DOTA-N-T20.3 to target NTSR1 in vivo. PET imaging was also conducted in an orthotopic xenograft model that allows tumors to grow in their native microenvironment and in an experimental pancreatitis model generated by caerulein injections. As opposed to 2-[ 18 F]fluoro-deoxyglucose, 68 Ga-DOTA-NT-20.3 distinguishes PDAC from pancreatitis. Thus, 68 Ga-DOTA-NT-20.3 is a promising PET imaging probe for imaging PDAC in humans.

Published
2019

38. IGF2/IR/IGF1R pathway in tumor cells and myofibroblasts mediates resistance to EGFR inhibition in cholangiocarcinoma

Author

Cédric Coulouarn, Audrey Clapéron, Cindy Lobe, Sylvana Tahraoui, Laura Fouassier, Dominique Wendum, Fatiha Merabtene, Christèle Desbois-Mouthon, Chantal Housset, Martine Mergey, Javier Vaquero, Françoise Praz, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Anatomie Pathologique [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), 2011 25574 and 2014 47502, Fondation de France, RS14/75-112), GEFLUC (2013), and ANR (ANR-17-CE14-0013-01, Ligue Contre le Cancer, Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-17-CE14-0013,EBPatobile,Régulation de l'homéostasie biliaire par la protéine d'échafaudage EBP50(2017), Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Nutrition, Métabolismes et Cancer ( NuMeCan ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Centre de Recherche Saint-Antoine ( UMRS893 )

Subjects
0301 basic medicine, Cancer Research, medicine.medical_treatment, [SDV]Life Sciences [q-bio], growth-factor receptor, Receptor, IGF Type 1, Cholangiocarcinoma, Mice, 0302 clinical medicine, Cancer-Associated Fibroblasts, cetuximab, Epidermal growth factor receptor, Myofibroblasts, biology, Chemistry, gemcitabine, 3. Good health, ErbB Receptors, Gene Expression Regulation, Neoplastic, Oncology, 030220 oncology & carcinogenesis, biliary-tract cancer, human hepatocellular-carcinoma, Heterografts, Erlotinib, Tyrosine kinase, Signal Transduction, medicine.drug, Cell signaling, insulin, Stromal cell, epithelial-mesenchymal transition, open-label, phase-2 trial, 03 medical and health sciences, Insulin-Like Growth Factor II, Cancer stem cell, Cell Line, Tumor, medicine, Animals, Humans, Protein Kinase Inhibitors, Cell Proliferation, Insulin-like growth factor 1 receptor, [ SDV ] Life Sciences [q-bio], Growth factor, oxaliplatin, Receptors, Somatomedin, Receptor, Insulin, respiratory tract diseases, 030104 developmental biology, Drug Resistance, Neoplasm, Cancer research, biology.protein
Abstract

Purpose: Cholangiocarcinoma (CCA) is a desmoplastic tumor of the biliary tree in which epidermal growth factor receptor (EGFR) is overexpressed and contributes to cancer progression. Although EGFR has been envisaged as a target for therapy, treatment with tyrosine kinase inhibitors (TKI) such as erlotinib did not provide therapeutic benefit in patients with CCA, emphasizing the need to investigate resistance mechanisms against EGFR inhibition. Experimental Design: Resistant CCA cells to EGFR inhibition were obtained upon long-time exposure of cells with erlotinib. Cell signaling, viability, migration, and spheroid growth were determined in vitro, and tumor growth was evaluated in CCA xenograft models. Results: Erlotinib-resistant CCA cells displayed metastasis-associated signatures that correlated with a marked change in cell plasticity associated with an epithelial–mesenchymal transition (EMT) and a cancer stem cell (CSC)–like phenotype. Resistant cells exhibited an upregulation of insulin receptor (IR) and insulin-like growth factor (IGF) 1 receptor (IGF1R), along with an increase in IGF2 expression. IR/IGF1R inhibition reduced EMT and CSC-like traits in resistant cells. In vivo, tumors developed from resistant CCA cells were larger and exhibited a more prominent stromal compartment, enriched in cancer-associated fibroblasts (CAF). Pharmacological coinhibition of EGFR and IR/IGF1R reduced tumor growth and stromal compartment in resistant tumors. Modeling of CCA-CAF crosstalk showed that IGF2 expressed by fibroblasts boosted IR/IGF1R signaling in resistant cells. Furthermore, IR/IGF1R signaling positively regulated fibroblast proliferation and activation. Conclusions: To escape EGFR-TKI treatment, CCA tumor cells develop an adaptive mechanism by undergoing an IR/IGF1R-dependent phenotypic switch, involving a contribution of stromal cells. Clin Cancer Res; 24(17); 4282–96. ©2018 AACR.

Published
2018

39. Influence of Progenitor-Derived Regeneration Markers on Hepatitis C Virus-Related Cirrhosis Outcome (ANRS CO12 CirVir Cohort)

Author

Carole Cagnot, Marianne Ziol, Nathalie Ganne-Carrié, Fatiha Merabtene, Françoise Roudot-Thoraval, Richard Layese, Christophe Sattonnet, Pierre Bedossa, Valérie Bourcier, Pierre Nahon, Benoit Terris, Paulette Bioulac-Sage, Dominique Wendum, Nathalie Barget, Janick Selves, Emmanuel Sauce, Nathalie Sturm, Service d'Anatomie et cytologie pathologiques [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Clinical Epidemiology and Ageing : Geriatrie Soins Primaires et Santé Publique (CEpiA), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de santé publique [Mondor], Université Paris-Est Créteil Val-de-Marne - Faculté de médecine (UPEC Médecine), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Sorbonne Paris Cité (USPC), Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Service d'Imagerie et de Cytométrie [CHU Saint-Antoine] (UMS LUMIC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), ANRS France Recherche Nord & sud Sida-hiv hépatites, Hôpital Beaujon [AP-HP], Service d'Anatomie et de cytologie pathologiques [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Centre Hospitalier Universitaire [Grenoble] (CHU), Gestionnaire, Hal Sorbonne Université, Service d'Anatomie Pathologique [CHU Saint-Antoine], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Liver Cirrhosis, Male, Cirrhosis, Hepacivirus, medicine.disease_cause, Gastroenterology, Cohort Studies, chemistry.chemical_compound, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Prospective Studies, intermediate hepatobiliary cells, liver decompensation, medicine.diagnostic_test, Stem Cells, Hazard ratio, Biopsy, Needle, Epithelial cell adhesion molecule, hepatocellular carcinoma, Middle Aged, Epithelial Cell Adhesion Molecule, Prognosis, Hepatitis C, Immunohistochemistry, 3. Good health, Survival Rate, Hepatocellular carcinoma, Liver biopsy, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Keratins, 030211 gastroenterology & hepatology, Female, Adult, medicine.medical_specialty, Hepatitis C virus, Risk Assessment, 03 medical and health sciences, Internal medicine, medicine, Humans, Decompensation, Aged, Proportional Hazards Models, Hepatology, business.industry, Keratin7, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Liver Regeneration, 030104 developmental biology, chemistry, EpCAM, Multivariate Analysis, business, Biomarkers
Abstract

Progenitor-derived regeneration gives rise to the aberrant expression of biliary markers such as cytokeratin 7 (K7) and epithelial cell adhesion molecule (EpCAM) in hepatocytes. We aimed to describe the expression of these molecules in patients with compensated hepatitis C virus (HCV)-related cirrhosis and to investigate its potential influence on cirrhosis complications. Among patients with Child-Pugh A uncomplicated HCV-related cirrhosis enrolled in the prospective ANRS CO12 CirVir cohort, we selected individuals with a liver biopsy collected within 2 years before inclusion in the study. K7 and EpCAM immunostaining identified intermediate hepatobiliary cells. The influence of biliary marker expres-sion in hepatocytes on decompensation events and the occurrence of hepatocellular carcinoma (HCC) was studied using a multivariate Cox proportional hazards regression model. Among the 337 patients eligible for the study (men, 67%; median age, 52 years), 198 (58.8%) had biopsies with K7-positive hepatocytes including extensive staining in 40 (11.9%) and 203 had EpCAM-positive hepatocytes (60.6%). During follow-up (median, 54.2 months), 47 patients (14%) experienced a decompensation event, and HCC was diagnosed in 37 patients (11%). Extensive K7 staining was independently associated with the occurrence of a decompensation event (hazard ratio [HR], 3.00; 95% confidence interval [CI], 1.30-6.89; P = 0.010). EpCAM expression was independently associated with HCC occurrence (HR, 2.37; 95% CI, 1.07-5.23; P =0.033) along with age and a low prothrombin ratio. CONCLUSION Progenitor-derived regeneration depicted by K7 and EpCAM immunostaining of hepatocytes in liver biopsies of patients with compensated HCV-related cirrhosis marks a cirrhosis stage more prone to develop complications. (HEPATOLOGY 2018; 68:1534-1548).

Published
2018

40. La cholangite à lésion épithéliale granulocytique : une nouvelle entité avec un traitement spécifique

Author

Valérie Dhalluin-Venier, Christophe Corpechot, Jessica Calvo, Lionel Arrivé, and Dominique Wendum

Subjects
Pathology and Forensic Medicine
Abstract

Resume Nous rapportons un cas de cholangite a lesion epitheliale granulocytique associee a une pancreatite chez un homme de 22 ans. L’association d’une cholangite a une augmentation du volume du pancreas evoque en premier lieu une cholangite a IgG4 associee a une pancreatite auto-immune de type I (a IgG4). Cependant, nous n’avons trouve aucun infiltrat tissulaire a IgG4 et il existait une cholangite a lesion epitheliale granulocytique sur la biopsie hepatique. Recemment, la cholangite a lesion epitheliale granulocytique, dont les lesions ressemblent aux lesions microscopiques de la pancreatite auto-immune de type II, a ete decrite. La possibilite d’une entite commune regroupant des lesions biliaires et la pancreatite auto-immune de type II est proposee dans la litterature. Cette affection est retrouvee dans environ 2 % des cas ayant un tableau de cholangite sclerosante. Elle touche plus volontiers les enfants et les adultes jeunes, serait souvent associee a la presence d’une maladie inflammatoire chronique intestinale et parfois d’une pancreatite. Cette entite est definie histologiquement par la presence sur la biopsie hepatique de lesions epitheliales granulocytiques au niveau des canaux biliaires. Cette forme particuliere de cholangite, contrairement a la cholangite sclerosante primitive, repond tres bien au traitement par corticoides d’ou l’importance de son diagnostic.

Published
2015

41. Portal myofibroblasts promote vascular remodeling underlying cirrhosis formation through the release of microparticles

Author

Chantal M. Boulanger, Axelle Cadoret, Colette Rey, Christophe Corpechot, Chantal Housset, Véronique Barbu, Dominique Thabut, Pierre-Emmanuel Rautou, Nelly Bosselut, Sara Lemoinne, Haquima El Mourabit, Gérard Feldmann, Dominique Wendum, Vlad Ratziu, and Corneliu Henegar

Subjects
Pathology, medicine.medical_specialty, Hepatology, Liver cytology, Angiogenesis, Biology, Umbilical vein, Mural cell, Vascular endothelial growth factor, chemistry.chemical_compound, Vascular endothelial growth factor A, Canals of Hering, chemistry, Hepatic stellate cell, medicine
Abstract

Liver fibrosis expanding from portal tracts and vascular remodeling are determinant factors in the progression of liver diseases to cirrhosis. In the present study, we examined the potential contribution of portal myofibroblasts (PMFs) to the vascular changes leading to cirrhosis. The analyses of liver cells based on the transcriptome of rat PMFs, compared to hepatic stellate cell HSC-derived myofibroblasts in culture, identified collagen, type XV, alpha 1 (COL15A1) as a marker of PMFs. Normal liver contained rare COL15A1-immunoreactive cells adjacent to the bile ducts and canals of Hering in the portal area. A marked increase in COL15A1 expression occurred together with that of the endothelial marker, von Willebrand factor, in human and rat liver tissue, at advanced stages of fibrosis caused by either biliary or hepatocellular injury. In cirrhotic liver, COL15A1-expressing PMFs adopted a perivascular distribution outlining vascular capillaries proximal to reactive ductules, within large fibrotic septa. The effect of PMFs on endothelial cells (ECs) was evaluated by in vitro and in vivo angiogenesis assays. PMF-conditioned medium increased the migration and tubulogenesis of liver ECs as well as human umbilical vein ECs and triggered angiogenesis within Matrigel plugs in mice. In coculture, PMFs developed intercellular junctions with ECs and enhanced the formation of vascular structures. PMFs released vascular endothelial growth factor (VEGF)A-containing microparticles, which activated VEGF receptor 2 in ECs and largely mediated their proangiogenic effect. Cholangiocytes potentiated the angiogenic properties of PMFs by increasing VEGFA expression and microparticle shedding in these cells. Conclusion: PMFs are key cells in hepatic vascular remodeling. They signal to ECs through VEGFA-laden microparticles and act as mural cells for newly formed vessels, driving scar progression from portal tracts into the parenchyma. (Hepatology 2015;61:1041–1055)

Published
2015

42. Hepatocellular adenoma with malignant transformation in a patient with neonatal portal vein thrombosis

Author

Lionel Arrivé, Dominique Wendum, P. Balladur, and Jessica Zucman-Rossi

Subjects
Adenoma, Adult, Image-Guided Biopsy, Oncology, medicine.medical_specialty, Carcinoma, Hepatocellular, medicine.medical_treatment, Risk Assessment, Malignant transformation, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Biopsy, medicine, Carcinoma, Hepatectomy, Humans, Venous Thrombosis, Hepatology, medicine.diagnostic_test, Portal Vein, business.industry, Biopsy, Needle, Liver Neoplasms, Hepatocellular adenoma, medicine.disease, Immunohistochemistry, Magnetic Resonance Imaging, Portal vein thrombosis, Venous thrombosis, Cell Transformation, Neoplastic, Treatment Outcome, 030220 oncology & carcinogenesis, Female, 030211 gastroenterology & hepatology, Radiology, business, Follow-Up Studies
Published
2016

43. Hepatic epithelioid hemangioendothelioma

Author

Lionel Arrivé, Claire Goumard, Dominique Wendum, Athena Galletto Pregliasco, Ospedali Galliera, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Adult, Pathology, medicine.medical_specialty, Hepatology, business.industry, Liver Neoplasms, Gastroenterology, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, Hepatic Epithelioid Hemangioendothelioma, 3. Good health, Hemangioendothelioma, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, medicine, Hemangioendothelioma, Epithelioid, Humans, Female, 030211 gastroenterology & hepatology, business, Epithelioid hemangioendothelioma
Abstract

International audience; A 36-year-old woman with no relevant medical or surgical history was referred to our attention for abdominal diffuse pain and mild weight loss. No risk factors such as hepatitis, alcohol abuse, oral contraceptive use, or a family history of carcinoma were reported. Liver laboratory studies were unremarkable, except for elevated gamma-glutamyl transferase (138 U/L). Viral serology tests were negative, as were serum carcinoembryonic antigen, CA 19-9, and alpha-fetoprotein.

Published
2016

44. Low Levels of Microsatellite Instability at Simple Repeated Sequences Commonly Occur in Human Hepatocellular Carcinoma

Author

Françoise Praz, Dominique Wendum, Fatiha Merabtene, Christèle Desbois-Mouthon, Claire Calmel, Olivier Scatton, Claire Goumard, Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie Pathologique [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Anatomie et cytologie pathologiques [CHU Saint-Antoine], and HAL-UPMC, Gestionnaire

Subjects
Adult, Male, 0301 basic medicine, Cancer Research, Pathology, medicine.medical_specialty, Carcinoma, Hepatocellular, Cirrhosis, Adolescent, Context (language use), [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Polymerase Chain Reaction, Biochemistry, law.invention, Young Adult, 03 medical and health sciences, Liver disease, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, law, Genetics, medicine, Humans, Molecular Biology, neoplasms, Polymerase chain reaction, Aged, Aged, 80 and over, Liver Neoplasms, Microsatellite instability, Middle Aged, medicine.disease, Phenotype, digestive system diseases, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Microsatellite, Female, Microsatellite Instability, Research Article, Microsatellite Repeats
Abstract

International audience; Background/Aim: The aim of this study was to assess the incidence of MSI in a large series of human hepatocellular carcinomas (HCC) with various etiologies. Materials and Methods: The MSI status was determined by polymerase chain reaction (PCR) using 5 mononucleotide and 13 CAn dinucleotide repeats. Results: None of the 122 HCC samples displayed an MSI-High phenotype, as defined by the presence of alterations at more than 30% of the microsatellite markers analyzed. Yet, limited microsatellite instability consisting in the insertion or deletion of a few repeat motifs was detected in 32 tumor samples (26.2%), regardless of the etiology of the underlying liver disease. MSI tended to be higher in patients with cirrhosis (p=0.051), possibly reflecting an impact of the inflammatory context in this process. Conclusion: Based on a large series of HCC with various etiologies, our study allowed us to definitely conclude that MSI is not a hallmark of HCC.

Published
2017

45. Validation of the prognostic value of histologic scoring systems in primary sclerosing cholangitis: An international cohort study

Author

Christine Sempoux, Roger W. Chapman, Valérie Paradis, Ben Vainer, Benjamin Goeppert, Cyriel Y. Ponsioen, Astrid Kemgang, Peter Schirmacher, Stefan G. Hübscher, Kate D. Williamson, Annette S. H. Gouw, Johanna Arola, Joanne Verheij, Ulrich Beuers, Olivier Chazouillères, Katharina Biermann, Maren H. Harms, Gideon M. Hirschfield, Martti Färkkilä, Daniel Gotthardt, Elisabeth M.G. de Vries, Dominique Wendum, Henk R. van Buuren, Henriette Ytting, Palak J. Trivedi, Lai Mun Wang, Manon de Krijger, Groningen Institute for Organ Transplantation (GIOT), Gastroenterology & Hepatology, Pathology, Other departments, Graduate School, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and Gastroenterology and Hepatology

Subjects
medicine.medical_specialty, INTEROBSERVER, medicine.medical_treatment, LIVER FIBROSIS, Liver transplantation, Gastroenterology, STAGING SYSTEMS, Primary sclerosing cholangitis, 03 medical and health sciences, 0302 clinical medicine, Primary biliary cirrhosis, INFLAMMATION, Internal medicine, Medicine, Stage (cooking), Survival rate, PRIMARY BILIARY-CIRRHOSIS, Hepatology, business.industry, Proportional hazards model, Hazard ratio, CHRONIC HEPATITIS, medicine.disease, 3. Good health, 030220 oncology & carcinogenesis, BIOPSY, GRADING SYSTEM, 030211 gastroenterology & hepatology, OVERLAP SYNDROME, business, RISK-STRATIFICATION
Abstract

Histologic scoring systems specific for primary sclerosing cholangitis (PSC) are not validated. We recently determined the applicability and prognostic value of three histological scoring systems in a single PSC cohort. The aim of this study was to validate their prognostic use and reproducibility across a multicenter PSC cohort. Liver biopsies from PSC patients were collected from seven European institutions. Histologic scoring was performed using the Nakanuma, Ishak, and Ludwig scoring systems. Biopsies were independently scored by six liver pathologists for interobserver agreement. The prognostic value of clinical, biochemical, and all three histologic scoring systems on predicting composite endpoints 1 (PSC-related death and liver transplantation), 2 (liver transplantation), and 3 (liver-related events), was assessed using univariable and multivariable Cox proportional hazards modeling. A total of 119 PSC patients were identified, and the median follow-up was 142 months. During follow-up, 31 patients died (20 PSC-related deaths), 31 patients underwent liver transplantation, and 35 patients experienced one or more liver-related events. All three staging systems were independent predictors of endpoints 2 and 3 (Nakanuma system: hazard ratio [HR], 3.16 [95% confidence interval (CI), 1.49-6.68] for endpoint 2 and HR, 2.05 [95% CI, 1.17-3.57] for endpoint 3; Ishak system: HR, 1.55 [95% CI, 1.10-2.18] for endpoint 2 and HR, 1.43 [95% CI, 1.10-1.85] for endpoint 3; Ludwig system: HR, 2.62 [95% CI, 1.19-5.80] for endpoint 2 and HR, 2.06 [95% CI, 1.09-3.89] for endpoint 3). Only the Nakanuma staging system was independently associated with endpoint 1: HR, 2.14 (95% CI, 1.22-3.77). Interobserver agreement was moderate for Nakanuma stage (κ = 0.56) and substantial for Nakanuma component fibrosis (κ = 0.67), Ishak stage (κ = 0.64), and Ludwig stage (κ = 0.62). Conclusion: We confirm the independent prognostic value and demonstrate for the first time the reproducibility of staging disease progression in PSC using the Nakanuma, Ishak, and Ludwig staging systems. The Nakanuma staging system—incorporating features of chronic biliary disease—again showed the strongest predictive value. (Hepatology 2017;65:907-919).

Published
2017

46. Somatostatin receptors in resected hepatocellular carcinoma: status and correlation with markers of poor prognosis

Author

Jean-Luc Blachon, Mireille M. Bonnemaire, Sylvie Dumont, Fabien Schmidlin, Vandana Gupta, Dominique Wendum, Christèle Desbois-Mouthon, Olivier Scatton, Olivier Rosmorduc, Laetitia Fartoux, Marie Lequoy, Service d'hépatologie [Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM, Ipsen, CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Male, Poor prognosis, Pathology, medicine.medical_specialty, Carcinoma, Hepatocellular, Histology, Biology, Real-Time Polymerase Chain Reaction, SSTR2, Pathology and Forensic Medicine, law.invention, 03 medical and health sciences, 0302 clinical medicine, law, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Biomarkers, Tumor, medicine, Humans, Somatostatin receptor 2, Somatostatin receptor 1, Receptors, Somatostatin, neoplasms, Polymerase chain reaction, Somatostatin receptor, Liver Neoplasms, General Medicine, hepatocellular carcinoma, Middle Aged, HCCS, medicine.disease, digestive system diseases, 3. Good health, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, immunohistochemistry, liver resection, somatostatin receptors, Immunohistochemistry, Female, 030211 gastroenterology & hepatology, prognosis
Abstract

International audience; Aims: To investigate the status of somatostatin receptors (SSTRs) in resected hepatocellular carcinoma (HCC). Methods and results: Transcript and protein levels of SSTR2, SSTR3 and SSTR5 were investigated, with real-time polymerase chain reaction (PCR) and manual and automated immunohistochemistry (IHC), in 53 resected HCCs and paired non-tumour tissues. SSTR1, SSTR4, SSTR5TMD4 and SSTR5TMD5 were analysed with real-time PCR. SSTR3 and SSTR5 transcripts were expressed in similar to 25% of HCCs, but not in adjacent non-tumour tissues. SSTR1 and SSTR2 transcripts were overexpressed in 42% and 32% of HCCs, respectively. SSTR4, SSTR5TMD4 and SSTR5TMD5 were not detected. Membrane staining for SSTR2 was detected in 38% of HCCs, whereas SSTR5 protein was detectable in only 11% of HCCs. SSTR3 protein was detected in the majority of HCCs and adjacent non-tumour liver tissues, but membrane staining was

Published
2017

47. Molecular Classification of Hepatocellular Adenoma Associates With Risk Factors, Bleeding, and Malignant Transformation

Author

Viviane Gnemmi, Gabrielle Couchy, Jean-Frédéric Blanc, Eric Savier, Jean Saric, Georges-Philippe Pageaux, Christophe Letoublon, Jean-Charles Nault, Guillaume Morcrette, Valérie Vilgrain, Brigitte Le Bail, Denis Castaing, Christophe Laurent, Anne de Muret, Vincenzo Mazzaferro, Yannick Bacq, Alain Luciani, Julien Calderaro, Valérie Paradis, Laurence Chiche, Nora Frulio, Luigi Terraciano, Emmanuel Jacquemin, Emmanuel Boleslawski, Jeanne Ramos, Sandrine Imbeaud, Benoit Terris, Marie Christine Saint Paul, Brigitte Bancel, Jean-Christophe Vaillant, François Paye, Catherine Guettier, Jacques Belghiti, Janick Selves, Daniel Azoulay, Camilla Pilati, Eric Letouzé, Dominique Wendum, Stefano Caruso, Charles Balabaud, Pascal Bourlier, Claire Castain, Jean-Michel Fabre, Jessica Zucman-Rossi, Alexis Laurent, Sophie Prevot, Zin Benchellal, Fanny Dujardin, Monique Fabre, Sandra Rebouissou, Paulette Bioulac-Sage, Nathalie Sturm, Philippe Labrune, Jean-Marie Péron, Alberto Quaglia, Jean-Yves Scoazec, Université Paris 13 (UP13), Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie du cancer du foie, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Département d'hépato-gastro-entérologie [Hôpital Trousseau : CHRU Tours], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'Anatomo-Pathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut Gustave Roussy (IGR), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Département d'anatomie et cythologie pathologique, CHU Grenoble-Hôpital Michallon, Physiopathologie et traitement des maladies du foie, Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'anatomie pathologique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Service de Chirurgie Digestive, Hépato-Bilio-pancréatique et Transplantation Hépatique [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Thérapie génique, Génomique et Epigénomique (U 1169), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie Pathologique [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Service d'Anatomopathologie [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de pathologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service d'oncologie médicale [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Anatomie et cytologie pathologiques [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)-CHU Trousseau [APHP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Paul Brousse-Université Paris-Sud - Paris 11 (UP11), CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-CHU Trousseau [APHP], Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), CHU Necker - Enfants Malades [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Malignant transformation, 0302 clinical medicine, Risk Factors, Cytokine Receptor gp130, GTP-Binding Protein alpha Subunits, Gs, Hepatocyte Nuclear Factor 1-alpha, Child, Telomerase, beta Catenin, Inhibin-beta Subunits, Aged, 80 and over, biology, Liver Neoplasms, Gastroenterology, hepatocellular carcinoma, Middle Aged, Protein-Tyrosine Kinases, Neoplasm Proteins, 3. Good health, HNF1A, Cell Transformation, Neoplastic, 030220 oncology & carcinogenesis, Fyn-related kinase, Female, 030211 gastroenterology & hepatology, Gene Fusion, Signal Transduction, Adenoma, Adult, STAT3 Transcription Factor, Carcinoma, Hepatocellular, Adolescent, hepatocellular adenoma, Hemorrhage, Zinc Finger Protein GLI1, Young Adult, 03 medical and health sciences, sonic hedgehog, Chromogranins, GNAS complex locus, medicine, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, Hedgehog Proteins, benign liver tumor, Unclassified Hepatocellular Adenoma, Aged, Hepatology, Sequence Analysis, RNA, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Janus Kinase 2, Hepatocellular adenoma, medicine.disease, Mutation, biology.protein, Cancer research, Inflammatory Hepatocellular Adenoma, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Transcriptome
Abstract

International audience; BACKGROUND & AIMS: Hepatocellular adenomas (HCAs) are benign liver tumors that can be assigned to molecular subtypes based on inactivating mutations in hepatocyte nuclear factor 1A, activating mutations in β-catenin, or activation of inflammatory signaling pathways. We aimed to update the classification system for HCA and associate the subtypes with disease risk factors and complications.METHODS: We analyzed expression levels of 20 genes and sequenced exon regions of 8 genes (HNF1A, IL6ST, CTNNB1, FRK, STAT3, GNAS, JAK1, and TERT) in 607 samples of 533 HCAs from 411 patients, collected from 28 centers mainly in France from 2000 and 2014. We performed gene expression profile, RNA sequence, whole-exome and genome sequence, and immunohistochemical analyses of select samples. Molecular data were associated with risk factors, histopathology, bleeding, and malignant transformation.RESULTS: Symptomatic bleeding occurred in 14% of the patients (85% of cases were female, median age, 38 years); 7% of the nodules were borderline between HCA and hepatocellular carcinoma, and 3% of patients developed hepatocellular carcinoma from HCA. Based on molecular features, we classified HCA into 8 subgroups. One new subgroup, composed of previously unclassified HCA, represented 4% of HCAs overall and was associated with obesity and bleeding. These tumors were characterized by activation of sonic hedgehog signaling, due to focal deletions that fuse the promoter of INHBE with GLI1. Analysis of genetic heterogeneity among multiple HCAs, from different patients, revealed a molecular subtype field effect; multiple tumors had different mutations that deregulated similar pathways. Specific molecular subtypes of HCA associated with various HCA risk factors, including imbalances in estrogen or androgen hormones. Specific molecular subgroup of HCA with β-catenin and sonic hedgehog activation associated with malignant transformation and bleeding, respectively.CONCLUSIONS: Using sequencing and gene expression analyses, we identified a subgroup of HCA characterized by fusion of the INHBE and GLI1 genes and activation of sonic hedgehog pathway. Molecular subtypes of HCAs associated with different patients' risk factors for HCA, disease progression, and pathology features of tumors. This classification system might be used to select treatment strategies for patients with HCA.

Published
2017

48. Metastasis suppressor NM23 limits oxidative stress in mammals by preventing activation of stress-activated protein kinases/JNKs through its nucleoside diphosphate kinase activity

Author

Michel Lepoivre, Isabelle Moranvillier, Evelyne Peuchant, François Moreau-Gaudry, Sandrine Dabernat, Jérôme Guitton, Mathieu Boissan, Dominique Wendum, Marie-Lise Bats, Marie-Lise Lacombe, Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Laboratoire Bioénergétique Membranaire et Stress (LBMS), Département Biochimie, Biophysique et Biologie Structurale (B3S), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, MAPK/ERK pathway, Keratinocytes, Male, Paraquat, MAP Kinase Signaling System, [SDV]Life Sciences [q-bio], keratinocyte, medicine.disease_cause, NDPK, Biochemistry, Cell Line, 03 medical and health sciences, Mice, Genetics, medicine, hepatocyte, Animals, Humans, ASK1, Metastasis suppressor, Molecular Biology, Cells, Cultured, Kinase, Chemistry, Article RECHERCHE, Fibroblasts, NM23 Nucleoside Diphosphate Kinases, Molecular biology, MAPK, Nucleoside-diphosphate kinase, Mice, Inbred C57BL, Oxidative Stress, 030104 developmental biology, Liver, Cell culture, Hepatocytes, Nucleoside, Oxidative stress, Gene Deletion, Biotechnology
Abstract

NME1 (nonmetastatic expressed 1) gene, which encodes nucleoside diphosphate kinase (NDPK) A [also known as nonmetastatic clone 23 (NM23)-H1 in humans and NM23-M1 in mice], is a suppressor of metastasis, but several lines of evidence-mostly from plants-also implicate it in the regulation of the oxidative stress response. Here, our aim was to investigate the physiologic relevance of NDPK A with respect to the oxidative stress response in mammals and to study its molecular basis. NME1-knockout mice died sooner, suffered greater hepatocyte injury, and had lower superoxide dismutase activity than did wild-type (WT) mice in response to paraquat-induced acute oxidative stress. Deletion of NME1 reduced total NDPK activity and exacerbated activation of the stress-related MAPK, JNK, in the liver in response to paraquat. In a mouse transformed hepatocyte cell line and in primary cultures of normal human keratinocytes, MAPK activation in response to H2O2 and UVB, respectively, was dampened by expression of NM23-M1/NM23-H1, dependent on its NDPK catalytic activity. Furthermore, excess or depletion of NM23-M1/NM23-H1 NDPK activity did not affect the intracellular bulk concentration of nucleoside di- and triphosphates. NME1-deficient mouse embryo fibroblasts grew poorly in culture, were more sensitive to stress than WT fibroblasts, and did not immortalize, which suggested that they senesce earlier than do WT fibroblasts. Collectively, these results indicate that the NDPK activity of NM23-M1/NM23-H1 protects cells from acute oxidative stress by inhibiting activation of JNK in mammal models.-Peuchant, E., Bats, M.-L., Moranvillier, I., Lepoivre, M., Guitton, J., Wendum, D., Lacombe, M.-L., Moreau-Gaudry, F., Boissan, M., Dabernat, S. Metastasis suppressor NM23 limits oxidative stress in mammals by preventing activation of stress-activated protein kinases/JNKs through its nucleoside diphosphate kinase activity.

Published
2017

49. Insulin receptor isoform A is a new player in the progression of hepatocellular carcinoma

Author

Françoise Praz, Olivier Rosmorduc, C. Yves, Z. Salame, Laetitia Fartoux, Olivier Scatton, Dominique Wendum, Christèle Desbois-Mouthon, Fatiha Merabtene, Eva Benabou, Sylvana Tahraoui, Laura Fouassier, and Marie Lequoy

Subjects
Gene isoform, Insulin receptor, Hepatology, biology, business.industry, Hepatocellular carcinoma, medicine, biology.protein, Cancer research, medicine.disease, business
Published
2018

50. Hepatic myofibroblasts promote the progression of human cholangiocarcinoma through activation of epidermal growth factor receptor

Author

Dominique Wendum, Fatiha Merabtene, Christèle Desbois-Mouthon, Laura Fouassier, Chantal Housset, Martine Mergey, Audrey Clapéron, Lynda Aoudjehane, Thanh Huong Nguyen Ho-Bouldoires, Olivier Scatton, Filomena Conti, Delphine Firrincieli, and Aurélie Prignon

Subjects
Pathology, medicine.medical_specialty, Stromal cell, Hepatology, biology, Heparin-binding EGF-like growth factor, Transforming growth factor beta, Paracrine signalling, Gefitinib, Epidermal growth factor, parasitic diseases, Cancer cell, biology.protein, Cancer research, medicine, cardiovascular diseases, Epidermal growth factor receptor, medicine.drug
Abstract

Intrahepatic cholangiocarcinoma (CCA) is characterized by an abundant desmoplastic environment. Poor prognosis of CCA has been associated with the presence of alpha-smooth muscle actin (α-SMA)-positive myofibroblasts (MFs) in the stroma and with the sustained activation of the epidermal growth factor receptor (EGFR) in tumor cells. Among EGFR ligands, heparin-binding epidermal growth factor (HB-EGF) has emerged as a paracrine factor that contributes to intercellular communications between MFs and tumor cells in several cancers. This study was designed to test whether hepatic MFs contributed to CCA progression through EGFR signaling. The interplay between CCA cells and hepatic MFs was examined first in vivo, using subcutaneous xenografts into immunocompromised mice. In these experiments, cotransplantation of CCA cells with human liver myofibroblasts (HLMFs) increased tumor incidence, size, and metastastic dissemination of tumors. These effects were abolished by gefitinib, an EGFR tyrosine kinase inhibitor. Immunohistochemical analyses of human CCA tissues showed that stromal MFs expressed HB-EGF, whereas EGFR was detected in cancer cells. In vitro, HLMFs produced HB-EGF and their conditioned media induced EGFR activation and promoted disruption of adherens junctions, migratory and invasive properties in CCA cells. These effects were abolished in the presence of gefitinib or HB-EGF-neutralizing antibody. We also showed that CCA cells produced transforming growth factor beta 1, which, in turn, induced HB-EGF expression in HLMFs. Conclusion: A reciprocal cross-talk between CCA cells and myofibroblasts through the HB-EGF/EGFR axis contributes to CCA progression. (Hepatology 2013; 58:2001–2011)

Published
2013

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