Team 04 - Helicobacter-associated digestive cancers, cancer stem cells and therapeutic strategies

Équipe 04 – Cancers digestifs associés à l’infection par Helicobacter, cellules souches cancéreuses et stratégies thérapeutiques

Our team has a long history and international recognition in the field of Helicobacter infection, inflammation and gastric cancer. The team has grown since its initial creation in 2007 and currently has ~25 people including 14 teacher-researchers, researchers and clinicians from different disciplines (bacteriology, digestive surgery, anatomopathology, geriatrics, interventional radiology). Our research projects concern 1) the modeling of digestive cancers of infectious origin, for the identification of the molecular mechanisms involved and the role of the microbiota in carcinogenesis and the response to treatment, and 2) the development of new diagnostic and therapeutic strategies in oncology, with a particular focus on cancer stem cells at the origin of chemoresistance and metastatic dissemination. Images propriété de l'équipe 4These images are the property of team 4.


Keywords

gastric cancer, inflammation, cancer stem cells, microbiota, bacterial toxins, therapeutic strategies, biomarker, cell signalling, mouse models, histopathology, molecular imaging

News


Projects

Targeting the circulating tumor microenvironment in gastric cancer : focus on the interactions between cancer stem cells and myeloid derived suppressor cells

Gastric cancer (GC) is the 4th leading cause of cancer death worldwide. Team 1 identified and characterized cancer stem cells (CSCs) driving tumor initiation and chemoresistance in GC, including a mesenchymal subpopulation of CSCs detected as circulating tumor cells (CTCs) and metastatic. Dissemination of CTCs is particularly inefficient, and only a fraction can survive and act as metastasis initiating cells (MIC). These CTCs are detected alone or associated with pro-tumor immune cells such as neutrophils and/or immunosuppressive myeloid cells (MDSC). Team 2 extensively investigated the multiple tumor promoting functions of MDSCs.

Our hypothesis is that MDSCs can associate with CTCs, promote the properties of CSCs, protect MICs in the blood and promote their metastatic seeding. This project aims: 1) to identify biomarkers and signaling pathways of CSCs/MICs and 2) to explore, model and target CTCs/myeloid cell interactions and their impacts on the phenotype, tumorigenic, metastatic and resistance properties of CSCs/ MIC. Methods: cell lines and xenografts, liquid biopsies (CTC), myeloid cell/CSC cocultures, omics, bioinformatics, in vitro functional studies and xenografts, patient tissues.

The results of this project will lead to 1) the identification of new markers of GC CSCs/MICs for diagnostic, prognostic and therapeutic purposes, 2) the characterization of immune cells forming clusters with CTCs allowing to decipher and target their promoting action of CSC/MIC properties, 3) identifying new diagnostic and prognostic tools and developing innovative therapeutic strategies targeting CSC/MIC-MDSC interactions in the GC.

This project is carried out in collaboration with the team of Pr. Nicolas Larmonier, ImmunoConcEpt CNRS 5134, University of Bordeaux, and is financially supported by the Impulsion Newmoon network and the ITMO Cancer Aviesan Inserm.


Project members

Noteworthy publications
Characterization of Biomarkers of Tumorigenic and Chemoresistant Cancer Stem Cells in Human Gastric Carcinoma.
Nguyen PH, Giraud J, Chambonnier L, Dubus P, Wittkop L, Belleannée G, Collet D, Soubeyran I, Evrard S, Rousseau B, Senant-Dugot N, Mégraud F, Mazurier F, Varon C
Clinical cancer research : an official journal of the American Association for Cancer Research ; 2017 Mar 15
Orthotopic Patient-Derived Xenografts of Gastric Cancer to Decipher Drugs Effects on Cancer Stem Cells and Metastatic Dissemination.
Giraud J, Bouriez D, Seeneevassen L, Rousseau B, Sifré E, Giese A, Mégraud F, Lehours P, Dubus P, Gronnier C, Varon C
Cancers ; 2019 Apr 19
Verteporfin targeting YAP1/TAZ-TEAD transcriptional activity inhibits the tumorigenic properties of gastric cancer stem cells.
Giraud J, Molina-Castro S, Seeneevassen L, Sifré E, Izotte J, Tiffon C, Staedel C, Boeuf H, Fernandez S, Barthelemy P, Megraud F, Lehours P, Dubus P, Varon C
International journal of cancer ; 2020 Apr 15
Leukaemia Inhibitory Factor (LIF) Inhibits Cancer Stem Cells Tumorigenic Properties through Hippo Kinases Activation in Gastric Cancer.
Seeneevassen L, Giraud J, Molina-Castro S, Sifré E, Tiffon C, Beauvoit C, Staedel C, Mégraud F, Lehours P, Martin OCB, Boeuf H, Dubus P, Varon C
Cancers ; 2020 Jul 22
Metformin targets gastric cancer stem cells.
Courtois S, Durán RV, Giraud J, Sifré E, Izotte J, Mégraud F, Lehours P, Varon C, Bessède E
European journal of cancer (Oxford, England : 1990) ; 2017 Oct 01

Helicobacter and microbiota in gastric MALT lymphomagenesis

  1. pylori can induce gastric MALT lymphoma because of constant stimulation of antigen presentation leading to B cell expansion. Our working hypothesis is that a Helicobacter/Escherichia coli-coinfection promotes gastric lymphomagenesis.

The gastric and intestinal microbiota will be explored. Bacteriological, histological, molecular and metagenomic analyzes will allow us to answer several questions:

-does E. coli infection favor Helicobacter-induced gastric lymphomagenesis?

-does E. coli infection influence the gastric inflammatory response?

-are the virulence factors of E. coli, in particular colibactin, involved in these processes?

Our experimental approaches by metagenomics will allow to identify the nature of taxa and or functions associated with these microbiota modifications.

In perspective, it will be of major interest to validate the taxonomic and functional modifications observed within the microbial community in murine model, in biopsies of patients suffering from gastric MALT lymphoma.

 

Collaborations: Pr MJ Blaser, Rutgers University, New Jersey; Pr R Bonnet, CHU Clermont Ferrand ;  Pr A Amiot, Hôpital Henri Mondor, Créteil, and Hôpital Saint Antoine, Paris-APHP; Pr B Huard, TRAIG, TIMC-IMAG, UMR 5525, university Grenoble-Alpes, La Tronche, France.


Project members

Noteworthy publications
APRIL-producing eosinophils are involved in gastric MALT lymphomagenesis induced by Helicobacter sp infection.
Blosse A, Peru S, Levy M, Marteyn B, Floch P, Sifré E, Giese A, Prochazkova-Carlotti M, Azzi Martin L, Dubus P, Mégraud F, Ruskone Fournestraux A, Fabiani B, Copie Bergman C, Robe C, Hahne M, Huard B, Lehours P
Scientific reports ; 2020 Sep 09
Deregulation of miRNA in Helicobacter pylori-Induced Gastric MALT Lymphoma: From Mice to Human.
Blosse A, Levy M, Robe C, Staedel C, Copie-Bergman C, Lehours P
Journal of clinical medicine ; 2019 Jun 13
A New Animal Model of Gastric Lymphomagenesis: APRIL Transgenic Mice Infected by Helicobacter Species.
Floch P, Izotte J, Guillemaud J, Sifré E, Costet P, Rousseau B, Laur AM, Giese A, Korolik V, Mégraud F, Dubus P, Hahne M, Lehours P
The American journal of pathology ; 2017 Jul 01
Characterisation of inflammatory processes in Helicobacter pylori-induced gastric lymphomagenesis in a mouse model.
Floch P, Laur AM, Korolik V, Chrisment D, Cappellen D, Idrissi Y, Dubus P, Mégraud F, Lehours P
Oncotarget ; 2015 Oct 27
Neonatal thymectomy favors Helicobacter pylori-promoted gastric mucosa-associated lymphoid tissue lymphoma lesions in BALB/c mice.
Chrisment D, Dubus P, Chambonnier L, Hocès de la Guardia A, Sifré E, Giese A, Capone M, Khairallah C, Costet P, Rousseau B, Hubert C, Burlen-Defranoux O, Varon C, Bandeira A, Mégraud F, Lehours P
The American journal of pathology ; 2014 Aug 01

Identification of the cellular and molecular mechanisms involved in the pro-tumoral function of tuft cells in Helicobacter-triggered gastric cancer - towards novel therapeutic avenues

Gastric cancer is the 5th most common diagnosed cancer and the 4th cause of cancer-related deaths worldwide according to the latest report of the International Agency for Research on Cancer . Gastric carcinoma are more often diagnosed at an advanced stage, with limited therapeutic options and a high rate of recurrence post treatment, leading to a poor 5-years overall survival. Helicobacter pylori (H. pylori) is a gram-negative bacterium that colonizes the human stomach. Epidemiological surveys estimate that chronic infection by this bacteria constitutes is the main causative agent of gastric cancer . Helicobacter infection induces changes of the gastric mucosa leading over time to invasive carcinoma in approximately 1% of the cases. A better understand of the early phases of mucosal changes caused by chronic Helicobacter infection and leading to carcinogenesis is essential to inhibit or reverse such changes and prevent transformation. The recent characterization of gastro-intestinal tuft cells has opened up novel opportunities in the field of gastric cancer biology. The team of P Jay (IGF Montpellier) discovered, together with others, the first function of intestinal tuft cells and their immune regulatory properties. More recently, Team 4 and P. Jay’s team established a collaboration to investigate the role of tuft cells in the gastric physiopathology following Helicobacter infection, using a mouse model that specifically lacks tuft cells. The main objectives of this collaborative project are (1) to discover the mechanisms involved in the pro-inflammatory and pro-tumoral properties of gastric tuft cells using relevant innovative mouse models, and (2) to establish how our findings apply to the human disease, and whether the mechanisms identified in mouse models may constitute attractive drug targets or useful biomarkers. This collaborative project involving P. Jay’s team in Montpellier and C. Varon’s team 4 in Bordeaux is supported by a national grant from the Association pour la Recherche contre le Cancer (labellisation de programme ARC 2021-2024).


Project members

Noteworthy publications
Helicobacter pylori infection recruits bone marrow-derived cells that participate in gastric preneoplasia in mice.
Varon C, Dubus P, Mazurier F, Asencio C, Chambonnier L, Ferrand J, Giese A, Senant-Dugot N, Carlotti M, Mégraud F
Gastroenterology ; 2012 Feb 01
Helicobacter pylori generates cells with cancer stem cell properties via epithelial-mesenchymal transition-like changes.
Bessède E, Staedel C, Acuña Amador LA, Nguyen PH, Chambonnier L, Hatakeyama M, Belleannée G, Mégraud F, Varon C
Oncogene ; 2014 Aug 07
Deletion of IQGAP1 promotes Helicobacter pylori-induced gastric dysplasia in mice and acquisition of cancer stem cell properties in vitro.
Bessède E, Molina S, Acuña-Amador L, Dubus P, Staedel C, Chambonnier L, Buissonnière A, Sifré E, Giese A, Bénéjat L, Rousseau B, Costet P, Sacks DB, Mégraud F, Varon C
Oncotarget ; 2016 Dec 06
The Hippo Kinase LATS2 Controls Helicobacter pylori-Induced Epithelial-Mesenchymal Transition and Intestinal Metaplasia in Gastric Mucosa.
Molina-Castro SE, Tiffon C, Giraud J, Boeuf H, Sifre E, Giese A, Belleannée G, Lehours P, Bessède E, Mégraud F, Dubus P, Staedel C, Varon C
Cellular and molecular gastroenterology and hepatology ; 2020 Jan 01
TAZ Controls Helicobacter pylori-Induced Epithelial-Mesenchymal Transition and Cancer Stem Cell-Like Invasive and Tumorigenic Properties.
Tiffon C, Giraud J, Molina-Castro SE, Peru S, Seeneevassen L, Sifré E, Staedel C, Bessède E, Dubus P, Mégraud F, Lehours P, Martin OCB, Varon C
Cells ; 2020 Jun 13

Modeling the role of the bacterial genotoxin cytolethal distending toxin in carcinogenesis

We are frequently exposed to infection with genotoxin-producing bacteria from the gut microbiota, such as cytolethal distending toxin (CDT) and colibactin.

These toxins cause severe DNA damage in host cells, well-known risk factor of cancer development and progression.

We are investigating the role of the bacterial genotoxin CDT in digestive carcinogenesis: epithelial to mesenchymal transition, autophagy, and cytoskeleton remodeling to establish the proof of the causal role of CDT in cancer to prove its carcinogenicity.

 


Project members

Noteworthy publications
The CDT of Helicobacter hepaticus induces pro-survival autophagy and nucleoplasmic reticulum formation concentrating the RNA binding proteins UNR/CSDE1 and P62/SQSTM1.
He W, Azzi-Martin L, Velasco V, Lehours P, Dubus P, Djavaheri-Mergny M, Ménard A
PLoS pathogens ; 2021 Mar 04
The Nuclear Remodeling Induced by Helicobacter Cytolethal Distending Toxin Involves MAFB Oncoprotein.
Péré-Védrenne C, He W, Azzi-Martin L, Prouzet-Mauléon V, Buissonnière A, Cardinaud B, Lehours P, Mégraud F, Grosset CF, Ménard A
Toxins ; 2020 Mar 12
Cytolethal distending toxin induces the formation of transient messenger-rich ribonucleoprotein nuclear invaginations in surviving cells.
Azzi-Martin L, He W, Péré-Védrenne C, Korolik V, Alix C, Prochazkova-Carlotti M, Morel JL, Le Roux-Goglin E, Lehours P, Djavaheri-Mergny M, Grosset CF, Varon C, Dubus P, Ménard A
PLoS pathogens ; 2019 Sep 30
The Cytolethal Distending Toxin Subunit CdtB of Helicobacter hepaticus Promotes Senescence and Endoreplication in Xenograft Mouse Models of Hepatic and Intestinal Cell Lines.
Péré-Védrenne C, Prochazkova-Carlotti M, Rousseau B, He W, Chambonnier L, Sifré E, Buissonnière A, Dubus P, Mégraud F, Varon C, Ménard A
Frontiers in cellular and infection microbiology ; 2017 Jun 30
The Cytolethal Distending Toxin Subunit CdtB of Helicobacter Induces a Th17-related and Antimicrobial Signature in Intestinal and Hepatic Cells In Vitro.
Péré-Védrenne C, Cardinaud B, Varon C, Mocan I, Buissonnière A, Izotte J, Mégraud F, Ménard A
The Journal of infectious diseases ; 2016 Jun 15

Study of the effects of the cytolethal distending toxin on cell differentiation and epithelial to mesenchymal transition


Project members

Noteworthy publications
The CDT of Helicobacter hepaticus induces pro-survival autophagy and nucleoplasmic reticulum formation concentrating the RNA binding proteins UNR/CSDE1 and P62/SQSTM1.
He W, Azzi-Martin L, Velasco V, Lehours P, Dubus P, Djavaheri-Mergny M, Ménard A
PLoS pathogens ; 2021 Mar 04
The Nuclear Remodeling Induced by Helicobacter Cytolethal Distending Toxin Involves MAFB Oncoprotein.
Péré-Védrenne C, He W, Azzi-Martin L, Prouzet-Mauléon V, Buissonnière A, Cardinaud B, Lehours P, Mégraud F, Grosset CF, Ménard A
Toxins ; 2020 Mar 12
Cytolethal distending toxin induces the formation of transient messenger-rich ribonucleoprotein nuclear invaginations in surviving cells.
Azzi-Martin L, He W, Péré-Védrenne C, Korolik V, Alix C, Prochazkova-Carlotti M, Morel JL, Le Roux-Goglin E, Lehours P, Djavaheri-Mergny M, Grosset CF, Varon C, Dubus P, Ménard A
PLoS pathogens ; 2019 Sep 30
The Cytolethal Distending Toxin Subunit CdtB of Helicobacter hepaticus Promotes Senescence and Endoreplication in Xenograft Mouse Models of Hepatic and Intestinal Cell Lines.
Péré-Védrenne C, Prochazkova-Carlotti M, Rousseau B, He W, Chambonnier L, Sifré E, Buissonnière A, Dubus P, Mégraud F, Varon C, Ménard A
Frontiers in cellular and infection microbiology ; 2017 Jun 30
The Cytolethal Distending Toxin Subunit CdtB of Helicobacter Induces a Th17-related and Antimicrobial Signature in Intestinal and Hepatic Cells In Vitro.
Péré-Védrenne C, Cardinaud B, Varon C, Mocan I, Buissonnière A, Izotte J, Mégraud F, Ménard A
The Journal of infectious diseases ; 2016 Jun 15

The Hippo/YAP/TAZ/TEAD signaling pathway in gastric carcinogenesis and cancer stem cells

Gastric adenocarcinoma is a cancer with a poor prognosis whose treatment, based essentially on surgery associated with conventional chemo/radiotherapy, is not very effective with a 5-year survival rate of less than 20%. Gastric tumors are heterogeneous and composed of cancer stem cells (CSC) responsible for tumor initiation, growth, dissemination and resistance to treatment. It is crucial to be able to find targeted therapies in order to increase the effectiveness of treatments. The main cause of gastric cancer is chronic infection with the bacterium Helicobacter pylori, which induces a series of pre-neoplastic changes in the gastric mucosa leading to the emergence of CSC. It has recently been demonstrated that the Hippo/YAP/TEAD signaling pathway is involved in controlling the properties of CSCs in breast and colon cancers. This signaling pathway is controlled by various upstream factors, including the Leukemia Inhibitory Factor (LIF) receptor (LIFR). The Hippo/YAP/TEAD pathway has recently been described in gastric cancer and we demonstrated that oncogenic effectors YAP/TAZ/TEAD are activated in response to H. pylori infection and lead to the emergence of gastric SCCs ( Molina-Castro et al, CMGH 2019, Tiffon et al, Cells 2020) and control their tumorigenic properties. We recently demonstrated that LIF treatment suppresses the ability of LIFR-expressing gastric cancer cells to form tumorspheres in vitro and decreases CD44 expression. This effect involves the activation of Hippo pathway kinases, repressing YAP1/TEAD transcriptional activity (Seeneevassen et al, Cancers 2020). We also showed that treatment with Verteporfin, a pharmacological inhibitor of YAP/TAZ interaction with the TEAD transcription factors, efficiently inhibits CSC phenotype and properties as well as tumor growth in xenograft models (Giraud et al, Int J Cancer 2019). Ongoing projects aim to determine whether targeting the Hippo pathway and YAP/TAZ/TEAD by different strategies can reduce the invasive and metastatic properties of gastric CSCs in vivo.


Project members

Noteworthy publications
Characterization of Biomarkers of Tumorigenic and Chemoresistant Cancer Stem Cells in Human Gastric Carcinoma.
Nguyen PH, Giraud J, Chambonnier L, Dubus P, Wittkop L, Belleannée G, Collet D, Soubeyran I, Evrard S, Rousseau B, Senant-Dugot N, Mégraud F, Mazurier F, Varon C
Clinical cancer research : an official journal of the American Association for Cancer Research ; 2017 Mar 15
The Hippo Kinase LATS2 Controls Helicobacter pylori-Induced Epithelial-Mesenchymal Transition and Intestinal Metaplasia in Gastric Mucosa.
Molina-Castro SE, Tiffon C, Giraud J, Boeuf H, Sifre E, Giese A, Belleannée G, Lehours P, Bessède E, Mégraud F, Dubus P, Staedel C, Varon C
Cellular and molecular gastroenterology and hepatology ; 2020 Jan 01
Leukaemia Inhibitory Factor (LIF) Inhibits Cancer Stem Cells Tumorigenic Properties through Hippo Kinases Activation in Gastric Cancer.
Seeneevassen L, Giraud J, Molina-Castro S, Sifré E, Tiffon C, Beauvoit C, Staedel C, Mégraud F, Lehours P, Martin OCB, Boeuf H, Dubus P, Varon C
Cancers ; 2020 Jul 22
TAZ Controls Helicobacter pylori-Induced Epithelial-Mesenchymal Transition and Cancer Stem Cell-Like Invasive and Tumorigenic Properties.
Tiffon C, Giraud J, Molina-Castro SE, Peru S, Seeneevassen L, Sifré E, Staedel C, Bessède E, Dubus P, Mégraud F, Lehours P, Martin OCB, Varon C
Cells ; 2020 Jun 13
Verteporfin targeting YAP1/TAZ-TEAD transcriptional activity inhibits the tumorigenic properties of gastric cancer stem cells.
Giraud J, Molina-Castro S, Seeneevassen L, Sifré E, Izotte J, Tiffon C, Staedel C, Boeuf H, Fernandez S, Barthelemy P, Megraud F, Lehours P, Dubus P, Varon C
International journal of cancer ; 2020 Apr 15

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Team’s noteworthy publications

Characterization of Biomarkers of Tumorigenic and Chemoresistant Cancer Stem Cells in Human Gastric Carcinoma.
Nguyen PH, Giraud J, Chambonnier L, Dubus P, Wittkop L, Belleannée G, Collet D, Soubeyran I, Evrard S, Rousseau B, Senant-Dugot N, Mégraud F, Mazurier F, Varon C
Clinical cancer research : an official journal of the American Association for Cancer Research ; 2017 Mar 15
The CDT of Helicobacter hepaticus induces pro-survival autophagy and nucleoplasmic reticulum formation concentrating the RNA binding proteins UNR/CSDE1 and P62/SQSTM1.
He W, Azzi-Martin L, Velasco V, Lehours P, Dubus P, Djavaheri-Mergny M, Ménard A
PLoS pathogens ; 2021 Mar 04


Partners

Team leaders

Christine VARON
Professor / PU


Team members

Lamia AZZI-MARTIN
Engineer / IE

Emilie BESSÈDE
Lecturer Clinician / MCU-PH

Franck COUILLAUD
Research Director / DR

Pierre DUBUS
Professor Clinician / PU-PH

Astrid DUCOURNAU
Technician / Tech

Christelle DUSSERT
Engineer Assistant / AI

Sandrine EIMER
Lecturer Clinician / MCU-PH

Coralie GENEVOIS
Engineer Assistant / AI

Alban GIESE
Engineer / IE

Nicolas GRENIER
Professor Clinician / PU-PH

Caroline GRONNIER
Professor Clinician / PU-PH

Jérome GUIGNARD
Technician / Tech

Marine JAUVAIN
PhD Student-Clin. Assist. / Doc-AHU

Quentin JEHANNE
PhD Student / Doc

Ruxue JIA
PhD Student / Doc

Philippe LEHOURS
Professor Clinician / PU-PH

Clément MARCELIN
PhD Student-Clin. Assist. / Doc-AHU

Francis MÉGRAUD
Professor Emeritus / PU émérite

Armelle MÉNARD
Research Engineer / IR

Fanny NEHME PELLUARD
Lecturer Clinician / MCU-PH

Jean PALUSSIÈRE
Clinician / PH

Claire ROUBAUD BAUDRON
Professor Clinician / PU-PH

Lornella SEENEEVASSEN
PhD Student / Doc

Elodie SIFRÉ
Engineer Assistant / AI

Christine VARON
Professor / PU