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1. Targeting metastasis-initiating cancer stem cells in gastric cancer with leukaemia inhibitory factor

Author

Seeneevassen, Lornella, Zaafour, Anissa, Sifré, Elodie, Genevois, Coralie, Nguyen, Tra Ly, Pobiedonoscew, Yasmine, Giese, Alban, Guignard, Jérôme, Tiffon, Camille, Rousseau, Benoit, Raymond, Anne-Aurélie, Belleannée, Geneviève, Boeuf, Hélène, Gronnier, Caroline, Martin, Océane C. B., Giraud, Julie, Lehours, Philippe, Dubus, Pierre, and Varon, Christine

Published
2024
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3. CD44v3 is a marker of invasive cancer stem cells driving metastasis in gastric carcinoma

Author

Giraud, Julie, Seeneevassen, Lornella, Rousseau, Benoit, Bouriez, Damien, Sifré, Elodie, Giese, Alban, Nguyen, Tra Ly, Tiffon, Camille, Lippi, Yannick, Azzi-Martin, Lamia, Pannequin, Julie, Ménard, Armelle, Bessède, Emilie, Staedel, Cathy, Mégraud, Francis, Belleannée, Geneviève, Lehours, Philippe, Gronnier, Caroline, Dubus, Pierre, and Varon, Christine

Published
2023
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11. CD44v3 is a marker of invasive cancer stem cells driving metastasis in gastric carcinoma

Author

Giraud, Julie, primary, Seeneevassen, Lornella, additional, Rousseau, Benoit, additional, Bouriez, Damien, additional, Sifré, Elodie, additional, Giese, Alban, additional, Nguyen, Tra Ly, additional, Tiffon, Camille, additional, Lippi, Yannick, additional, Azzi-Martin, Lamia, additional, Pannequin, Julie, additional, Ménard, Armelle, additional, Bessède, Emilie, additional, Staedel, Cathy, additional, Mégraud, Francis, additional, Belleannée, Geneviève, additional, Lehours, Philippe, additional, Gronnier, Caroline, additional, Dubus, Pierre, additional, and Varon, Christine, additional

Published
2022
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13. Nrf2 Downregulation Contributes to Epithelial-to-Mesenchymal Transition in Helicobacter pylori-Infected Cells

Author

Bacon, Sarah, primary, Seeneevassen, Lornella, additional, Fratacci, Alison, additional, Rose, Faustine, additional, Tiffon, Camille, additional, Sifré, Elodie, additional, Haykal, Maria M., additional, Moubarak, Maya M., additional, Ducournau, Astrid, additional, Bruhl, Lucie, additional, Claverol, Stéphane, additional, Tokarski, Caroline, additional, Gouloumi, Alina-Roxani, additional, Pateras, Ioannis S., additional, Daubon, Thomas, additional, Lehours, Philippe, additional, Varon, Christine, additional, and Martin, Océane C. B., additional

Published
2022
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15. Autophagy induced by Helicobacter pylori infection is necessary for gastric cancer stem cell emergence

Author

Ligue Nationale contre le Cancer (France), Courtois, Sarah, Haykal, Maria, Bodineau, Clément, Sifré, Elodie, Azzi-Martin, Lamia, Ménard, Armelle, Mégraud, Francis, Lehours, Philippe, Durán, Raúl V., Varon, Christine, Bessède, Emilie, Ligue Nationale contre le Cancer (France), Courtois, Sarah, Haykal, Maria, Bodineau, Clément, Sifré, Elodie, Azzi-Martin, Lamia, Ménard, Armelle, Mégraud, Francis, Lehours, Philippe, Durán, Raúl V., Varon, Christine, and Bessède, Emilie

Abstract

Background: The main cause of gastric cancer is the infection by the bacterium Helicobacter pylori which induces a chronic inflammation and an epithelial-to-mesenchymal transition (EMT) leading to the emergence of cells with cancer stem cell (CSC) properties. However, the underlying mechanisms have not been fully characterized. Moreover, H. pylori modulates the host cell autophagic process, but a few studies have investigated the role of this process in tumoral transformation. The aim of this study was to determine whether H. pylori-induced autophagy has a role in CSC emergence. Methods: Autophagic flux in response to H. pylori infection was characterized in AGS cell line expressing the tandem-tagged mCherry-GFP-LC3 protein and using a ratiometric flow cytometry analysis. Then, AGS and MKN45 cell lines were treated with bafilomycin or chloroquine, two pharmaceutical well-known inhibitors of autophagy, and different EMT and CSC characteristics were analyzed. Results: First, a co-expression of the gastric CSC marker CD44 and the autophagic marker LC3 in mice and human stomach tissues infected with H. pylori was observed. Then, we demonstrated in vitro that H. pylori was able to activate the autophagy process with a reduced autophagic flux. Finally, infected cells were treated with autophagy inhibitors, which reduced (i) appearance of mesenchymal phenotypes and migration ability related to EMT and (ii) CD44 expression as well as tumorsphere formation capacities reflecting CSC properties. Conclusion: In conclusion, all these data show that H. pylori-induced autophagy is implicated in gastric CSC emergence and could represent an interesting therapeutic target.

Published
2021

18. Leukaemia Inhibitory Factor (LIF) Inhibits Cancer Stem Cells Tumorigenic Properties through Hippo Kinases Activation in Gastric Cancer

Author

Seeneevassen, Lornella, primary, Giraud, Julie, additional, Molina-Castro, Silvia, additional, Sifré, Elodie, additional, Tiffon, Camille, additional, Beauvoit, Clémentine, additional, Staedel, Cathy, additional, Mégraud, Francis, additional, Lehours, Philippe, additional, Martin, Océane C.B., additional, Boeuf, Hélène, additional, Dubus, Pierre, additional, and Varon, Christine, additional

Published
2020
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19. TAZ Controls Helicobacter pylori-Induced Epithelial–Mesenchymal Transition and Cancer Stem Cell-Like Invasive and Tumorigenic Properties

Author

Tiffon, Camille, primary, Giraud, Julie, additional, Molina-Castro, Silvia Elena, additional, Peru, Sara, additional, Seeneevassen, Lornella, additional, Sifré, Elodie, additional, Staedel, Cathy, additional, Bessède, Emilie, additional, Dubus, Pierre, additional, Mégraud, Francis, additional, Lehours, Philippe, additional, Martin, Océane C.B., additional, and Varon, Christine, additional

Published
2020
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20. Helicobacter pylori infection induces mTORC1 inhibition in human gastric cancer cells

Author

Courtois, Sarah, Bodineau, Clément, Haykal, Maria, Sifré, Elodie, Azzi-Martin, Lamia, Mégraud, Francis, Lehours, Philippe, Varon, Christine, Durán, Raúl V., and Bessède, Emilie

Abstract

Trabajo presentado en la 27th UEG Week (United European Gastroenterology), celebrada en Barcelona (España), del 19 al 23 de octubre de 2019

Published
2019

21. Alzheimer’s Disease and Helicobacter pylori Infection: Inflammation from Stomach to Brain?

Author

Albaret, Guillaume, primary, Sifré, Elodie, additional, Floch, Pauline, additional, Laye, Sophie, additional, Aubert, Agnès, additional, Dubus, Pierre, additional, Azzi-Martin, Lamia, additional, Giese, Alban, additional, Salles, Nathalie, additional, Mégraud, Francis, additional, Varon, Christine, additional, Lehours, Philippe, additional, and Roubaud-Baudron, Claire, additional

Published
2020
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22. Verteporfin targeting YAP1/TAZ‐TEAD transcriptional activity inhibits the tumorigenic properties of gastric cancer stem cells

Author

Giraud, Julie, primary, Molina‐Castro, Silvia, additional, Seeneevassen, Lornella, additional, Sifré, Elodie, additional, Izotte, Julien, additional, Tiffon, Camille, additional, Staedel, Cathy, additional, Boeuf, Hélène, additional, Fernandez, Solène, additional, Barthelemy, Philippe, additional, Megraud, Francis, additional, Lehours, Philippe, additional, Dubus, Pierre, additional, and Varon, Christine, additional

Published
2019
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23. Orthotopic Patient-Derived Xenografts of Gastric Cancer to Decipher Drugs Effects on Cancer Stem Cells and Metastatic Dissemination

Author

Giraud, Julie, primary, Bouriez, Damien, additional, Seeneevassen, Lornella, additional, Rousseau, Benoit, additional, Sifré, Elodie, additional, Giese, Alban, additional, Mégraud, Francis, additional, Lehours, Philippe, additional, Dubus, Pierre, additional, Gronnier, Caroline, additional, and Varon, Christine, additional

Published
2019
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24. The Cytolethal Distending Toxin Subunit CdtB of Helicobacter hepaticus Promotes Senescence and Endoreplication in Xenograft Mouse Models of Hepatic and Intestinal Cell Lines

Author

Péré-Védrenne, Christelle, Prochazkova-Carlotti, Martina, Rousseau, Benoit, He, Wencan, Chambonnier, Lucie, Sifré, Elodie, Buissonnière, Alice, Dubus, Pierre, Mégraud, Francis, Varon, Christine, Ménard, Armelle, Bordeaux Research In Translational Oncology [Bordeaux] (BaRITOn), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Commun des Animaleries [Bordeaux], Université de Bordeaux (UB), and Varon, Christine

Subjects
[SDV] Life Sciences [q-bio], mitosis, endoreplication, senescence, [SDV]Life Sciences [q-bio], apoptosis, cytolethal distending toxin, Microbiology, Helicobacter hepaticus
Abstract

International audience; Cytolethal distending toxins (CDTs) are common among pathogenic bacteria of the human and animal microbiota. CDTs exert cytopathic effets, via their active CdtB subunit. No clear description of those cytopathic effects has been reported at the cellular level in the target organs in vivo. In the present study, xenograft mouse models of colon and liver cell lines were set up to study the effects of the CdtB subunit of Helicobacter hepaticus. Conditional transgenic cell lines were established, validated in vitro and then engrafted into immunodeficient mice. After successful engraftment, mice were treated with doxycyclin to induce the expression of transgenes (red fluorescent protein, CdtB, and mutated CdtB). For both engrafted cell lines, results revealed a delayed tumor growth and a reduced tumor weight in CdtB-expressing tumors compared to controls. CdtB-derived tumors showed γ-H2AX foci formation, an increase in apoptosis, senescence, p21 and Ki-67 nuclear antigen expression. No difference in proliferating cells undergoing mitosis (phospho-histone H3) was observed. CdtB intoxication was also associated with an overexpression of cytokeratins in cells at the invasive front of the tumor as well as an increase in ploidy. All these features are hallmarks of endoreplication, as well as aggressiveness in cancer. These effects were dependent on the histidine residue at position 265 of the CdtB, underlying the importance of this residue in CdtB catalytic activity. Taken together, these data indicate that the CdtB triggers senescence and cell endoreplication leading to giant polyploid cells in these xenograft mouse models.

Published
2017
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25. Verteporfin targeting YAP1/TAZ‐TEAD transcriptional activity inhibits the tumorigenic properties of gastric cancer stem cells.

Author

Giraud, Julie, Molina‐Castro, Silvia, Seeneevassen, Lornella, Sifré, Elodie, Izotte, Julien, Tiffon, Camille, Staedel, Cathy, Boeuf, Hélène, Fernandez, Solène, Barthelemy, Philippe, Megraud, Francis, Lehours, Philippe, Dubus, Pierre, and Varon, Christine

Subjects
CANCER stem cells, STOMACH cancer, TUMOR growth, TRANSCRIPTION factors, CELL proliferation
Abstract

Gastric carcinomas (GC) are heterogeneous tumors, composed of a subpopulation of cluster of differentiation‐44 (CD44)+ tumorigenic and chemoresistant cancer stem cells (CSC). YAP1 and TAZ oncoproteins (Y/T) interact with TEA domain family member 1 (TEAD) transcription factors to promote cell survival and proliferation in multiple tissues. Their activity and role in GC remain unclear. This work aimed to analyze Y/T‐TEAD activity and molecular signature in gastric CSC, and to assess the effect of verteporfin, a Food and Drug Administration‐approved drug preventing Y/T‐TEAD interaction, on gastric CSC tumorigenic properties. Y/T‐TEAD molecular signature was investigated using bioinformatical (KmPlot database), transcriptomic and immunostaining analyses in patient‐derived GC and cell lines. Verteporfin effects on Y/T‐TEAD transcriptional activity, CSC proliferation and tumorigenic properties were evaluated using in vitro tumorsphere assays and mouse models of patient‐derived GC xenografts. High expressions of YAP1, TAZ, TEAD1, TEAD4 and their target genes were associated with low overall survival in nonmetastatic human GC patients (n = 444). This Y/T‐TEAD molecular signature was enriched in CD44+ patient‐derived GC cells and in cells resistant to conventional chemotherapy. Verteporfin treatment inhibited Y/T‐TEAD transcriptional activity, cell proliferation and CD44 expression, and decreased the pool of tumorsphere‐forming CD44+/aldehyde dehydrogenase (ALDH)high gastric CSC. Finally, verteporfin treatment inhibited GC tumor growth in vivo; the residual tumor cells exhibited reduced expressions of CD44 and ALDH1, and more importantly, they were unable to initiate new tumorspheres in vitro. All these data demonstrate that Y/T‐TEAD activity controls gastric CSC tumorigenic properties. The repositioning of verteporfin targeting YAP1/TAZ‐TEAD activity could be a promising CSC‐based strategy for the treatment of GC. What's new? In gastric cancer, populations of cancer stem cells (CSCs), which initiate and sustain tumor growth and drive tumor recurrence, are maintained through activity of the yes‐associated protein 1 (YAP1), TAZ, and TEA domain transcription factor (TEAD) complex. In this study, employing gastric cancer models, transcriptional activity of the YAP1/TAZ‐TEAD complex was successfully inhibited by the benzoporphyrin derivative verteporfin. Specifically, verteporfin decreased the pool of gastric CSCs in vitro and in vivo and inhibited tumor growth in patient‐derived gastric cancer xenografts. The results suggest that targeting YAP1/TAZ‐TEAD activity with verteporfin is a promising therapeutic strategy for gastric cancer. [ABSTRACT FROM AUTHOR]

Published
2020
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26. Whole-Genome Sequence Analysis of Multidrug-Resistant Campylobacter Isolates: a Focus on Aminoglycoside Resistance Determinants

Author

Fabre, Adrien, primary, Oleastro, Monica, additional, Nunes, Alexandra, additional, Santos, Andrea, additional, Sifré, Elodie, additional, Ducournau, Astrid, additional, Bénéjat, Lucie, additional, Buissonnière, Alice, additional, Floch, Pauline, additional, Mégraud, Francis, additional, Dubois, Véronique, additional, and Lehours, Philippe, additional

Published
2018
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28. Occurrence and Antibiotic Resistance of ArcobacterSpecies Isolates from Poultry in Tunisia

Author

Jribi, Hela, Sellami, Hanen, Amor, Salha B., Ducournau, Astrid, Sifré, Elodie, Benejat, Lucie, Mégraud, Francis, and Gdoura, Radhouane

Abstract

Arcobacteris considered an emergent foodborne enteropathogen. Despite the high prevalence of this genus in poultry, the occurrence of Arcobacterspp. contamination in Tunisia remains unclear. The objectives of this study were (i) to isolate Arcobacterspecies (A. butzleriand A. cryaerophilus) by the culture method from different species of raw poultry meat, (ii) to verify the isolates by multiplex PCR (m-PCR) assay and matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS), and (iii) to determine the antibiotic resistance profiles of the isolates. A total of 250 poultry product samples (149 chicken and 101 turkey) were collected from various supermarkets in Sfax. The samples consisted of breasts, wings, legs, and neck skins. The overall isolation frequency of Arcobacterspp. was 10.4%. Arcobacterspp. were found in 13.42% of the chicken samples and in 5.49% of the turkey samples. All the acquired isolates were subject to detailed confirmation with subsequent species classification using m-PCR and MALDI-TOF MS. A. butzleriwas found in 22 samples (84.61%) and A. cryaerophilusin 4 samples (15.38%). Thus, m-PCR and MALDI-TOF MS were able to detect A. butzlerisignificantly better than the conventional method (χ2= 49.1 and P< 0.001). Arcobacterwas isolated from poultry in every season, at contamination levels of 30.76, 23.07, 19.23, and 26.92% in summer, spring, autumn, and winter, respectively. The disk diffusion method was used to determine the susceptibility of Arcobacterisolates to six antimicrobial drugs. All A. butzleriisolates (n= 24) were significantly resistant to erythromycin (P= 0.0015), ampicillin (P= 0.001), and ciprofloxacin (P= 0.05). All tested A. cryaerophilusstrains (n= 4) were susceptible to ampicillin, gentamicin, and amoxicillin–clavulanic acid. Multidrug resistance was observed in 83% of the Arcobacterspp. isolates. Our study detected Arcobacterspp. in Tunisian poultry; because of their multidrug resistance, these species may constitute a public health problem.

Published
2020
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29. Deletion of IQGAP1 promotes Helicobacter pylori-induced gastric dysplasia in mice and acquisition of cancer stem cell properties in vitro

Author

Bessède, Emilie, primary, Molina, Silvia, additional, Amador, Luis Acuña, additional, Dubus, Pierre, additional, Staedel, Cathy, additional, Chambonnier, Lucie, additional, Buissonnière, Alice, additional, Sifré, Elodie, additional, Giese, Alban, additional, Bénéjat, Lucie, additional, Rousseau, Benoît, additional, Costet, Pierre, additional, Sacks, David B., additional, Mégraud, Francis, additional, and Varon, Christine, additional

Published
2016
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33. Whole-Genome Sequence Analysis of Multidrug-Resistant CampylobacterIsolates: a Focus on Aminoglycoside Resistance Determinants

Author

Fabre, Adrien, Oleastro, Monica, Nunes, Alexandra, Santos, Andrea, Sifré, Elodie, Ducournau, Astrid, Bénéjat, Lucie, Buissonnière, Alice, Floch, Pauline, Mégraud, Francis, Dubois, Véronique, and Lehours, Philippe

Abstract

A whole-genome sequencing (WGS) approach was conducted in order to identify the molecular determinants associated with antimicrobial resistance in 12 multidrug-resistant Campylobacter jejuniand Campylobacter coliisolates, with a focus on aminoglycoside resistance determinants. Two variants of a new aminoglycoside phosphotransferase gene [aph(2?)-Ii1and aph(2?)-Ii2] putatively associated with gentamicin resistance were found.

Published
2018
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34. The Cytolethal Distending Toxin Subunit CdtB of Helicobacter hepaticus Promotes Senescence and Endoreplication in Xenograft Mouse Models of Hepatic and Intestinal Cell Lines.

Author

Péré-Védrenne C, Prochazkova-Carlotti M, Rousseau B, He W, Chambonnier L, Sifré E, Buissonnière A, Dubus P, Mégraud F, Varon C, and Ménard A

Subjects
Animals, Apoptosis, Bacterial Toxins metabolism, Cell Cycle drug effects, Cytoskeleton drug effects, Doxycycline pharmacology, Epithelial Cells, HT29 Cells drug effects, Heterografts, Histones metabolism, Humans, Ki-67 Antigen metabolism, Luminescent Proteins, Mice, Microbiota, Red Fluorescent Protein, Aging drug effects, Bacterial Toxins pharmacology, Cell Line, Tumor drug effects, Corneal Dystrophies, Hereditary metabolism, Endoreduplication drug effects, Helicobacter hepaticus metabolism, Intestines drug effects, Liver drug effects
Abstract

Cytolethal distending toxins (CDTs) are common among pathogenic bacteria of the human and animal microbiota. CDTs exert cytopathic effets, via their active CdtB subunit. No clear description of those cytopathic effects has been reported at the cellular level in the target organs in vivo . In the present study, xenograft mouse models of colon and liver cell lines were set up to study the effects of the CdtB subunit of Helicobacter hepaticus . Conditional transgenic cell lines were established, validated in vitro and then engrafted into immunodeficient mice. After successful engraftment, mice were treated with doxycyclin to induce the expression of transgenes (red fluorescent protein, CdtB, and mutated CdtB). For both engrafted cell lines, results revealed a delayed tumor growth and a reduced tumor weight in CdtB-expressing tumors compared to controls. CdtB-derived tumors showed γ-H2AX foci formation, an increase in apoptosis, senescence, p21 and Ki-67 nuclear antigen expression. No difference in proliferating cells undergoing mitosis (phospho-histone H3) was observed. CdtB intoxication was also associated with an overexpression of cytokeratins in cells at the invasive front of the tumor as well as an increase in ploidy. All these features are hallmarks of endoreplication, as well as aggressiveness in cancer. These effects were dependent on the histidine residue at position 265 of the CdtB, underlying the importance of this residue in CdtB catalytic activity. Taken together, these data indicate that the CdtB triggers senescence and cell endoreplication leading to giant polyploid cells in these xenograft mouse models.

Published
2017
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