At least 30% of cancers are linked to identified risk factors. More than one in six cases of cancer worldwide are caused by infection. Today, thanks to research into cancer-causing pathogens, Institut Pasteur researchers are developing new strategies for combating the cancers they cause. For example, the hepatitis B vaccine, which was developed at the Institut Pasteur, has prevented hundreds of thousands of cases of liver cancer in many countries. Developing new vaccines against cancer-causing pathogens is a major avenue for research. Furthermore, recent findings point to certain microbes or compounds of microbial origin as risk factors, whereas others appears has beneficial and would promote the efficacy of existing anti-cancer treatments such as chemotherapy or immunomodulators. Thus, researchers from Institut Pasteur study the molecular bases underlying the microbiom effects in order to identify and decrease of eliminate risk factors.
Department of Cell Biology & Infection
Jost-Enninga’s team works on the intracellular niche formation of bacterial pathogens including Salmonella and Shigella. These pathogens have been shown to crosstalk with major host cell pathways involved in cell transformation and cancer development. The scientists study why only some subpopulation of the infecting bacteria interfere with the singling events associated with cancer. It will lead to a better understanding of the links between intestinal cancer and food borne pathogens.
Pascal Pineau’s team is involved in a collaborative project (IRD, INEN) on hepatocellular carcinoma in children and adolescent from Peru. In this population with Native American ancestry, massive tumors are induced in absence of concomitant liver damage despite the constant presence of a stealth hepatitis B virus infection. His team is currently searching for the risk factor(s) that together with HBV might explain this peculiar tumor presentation. In parallel, Pascal Pineau is coordinating a project with Instituts Pasteur of Iran and Morocco on the role of the gut microbiota in liver tumorigenesis.
Key words : liver, hepatocellular carcinoma, hepatitis viruses, omics
Host-pathogen interactions shed light on metabolic changes occurring during tumorigenesis.
Some very peculiar bacteria, called intracellular bacteria because they multiply inside a “host” cell, have developed mechanisms to modify the metabolism of this host to meet their own needs. The project of this unit is based on the concept that some of these modifications are identical to those that occur during tumorigenesis, this time not to sustain bacterial growth but to feed the fast proliferation of cancer cells. Proof for thisconcept was brought by the demonstration that a human enzyme activated in many cancers, called transglutaminase 2, is also activated during infection by the intracellular human pathogen Chlamydia trachomatis. This research axis is being continued with the comparison of the consequences of the activation of transglutaminase 2 in cells infected with Chlamydia trachomatis and in ovarian cancer cells.
Key words : host-pathogen interactions, chlamydia trachomatis, metabolism, transglutaminase 2
Department of Immunology
Regulation of susceptibility to cancer by early life microbiota
The colonization of the intestine by the microbiota elicits a vigorous immune response termed the weaning reaction. This weaning reaction regulates the reactivity of the immune system and the susceptibility to inflammatory pathology later in life. In the absence of microbiota at weaning, excessive inflammation develops in the adult that significantly increase the incidence of colorectal cancer. This unit is now investigating the mechanisms that lead to excessive inflammation, and develop tools to inhibit the deregulation of the immune system and its consequences on cancer development.
Key words : microbiota, innate lymphoid cells, regulatory T cells, neuroimmunology
Department of Microbiology
Colorectal cancer (CRC) is the second-leading cause of cancer-related deaths in France and abroad. The aetiology of CRC is multifactorial, involving genetic and epigenetic alterations, chronic inflammatory processes and environmental stressors. In the human gut, dysbiotic microbiota or the chronic exposure to resident pathobionts can disturb intestinal tissue homeostasis thereby promoting CRC.
The Bacterial Toxins Unit at the Institut Pasteur is pursuing multidisciplinary research in collaboration with the CHU Henri Mondor (Oncomix-II project, labeled by the AP-HP) to go beyond microbiome-wide association studies towards causation and mechanistic studies that are aimed at characterizing the impact of combined chronic exposure to bacterial cyclomodulins and genotoxins that spread among Enterobacteriaceae, together with host genetic susceptibility background, in the aetiology of CRC.
Our research should lead to a better understanding of the mechanistic bases of the contribution of bacterial pathogens to oncogenesis, and will lay the foundations for transfer to the clinic.
Helicobacter pylori infection and gastric cancer
The objectives of our projects are to investigate the relationships between bacteria and cancer, using as a model system Helicobacter pylori infection and gastric cancer. Gastric cancer still remains the fifth most common cancer and the third leading cause of death by cancer in the world population. Its major risk factor is Helicobacter pylori which colonizes the stomach of about half of the human population. H. pylori is till now the only bacterium to be recognized as a type 1 carcinogenic agent. The mechanisms by which H. pylori causes gastric cancer are still poorly understood. Their study is an outstanding opportunity to better understand the relation between infection and cancer. Our projects combine both fundamental and translational aspects with the objectives to explore the mechanisms involved in the induction of cancer by H. pylori and to develop innovative diagnostic tools to prevent gastric cancer development.
• Host genotoxic response to H. pylori infection and gastric carcinogenesis
To further characterize essential events at the origin of the carcinogenesis process initiated by the presence of H. pylori, the mechanisms responsible for the genotoxic activity of H. pylori in host cells are particularly focused. In collaboration with MD Galibert’s team (University of Rennes, France), we recently characterized the transcription factor USF1 as a central regulator of the host DNA damage response to H. pylori and a modulator of gastric carcinogenesis (Costa et al, Gut 2020).
• Diagnostic tools to prevent gastric cancer
Gastric cancer is often detected at an advanced stage and mostly associated with a poor prognosis. It is only diagnosed by gastric endoscopy which does not always allow the detection of preneoplasia. The development of non-invasive methods such as blood-based biomarkers is also crucial to improve the prevention/detection of patients at risk of gastric cancer. We collaborated in an ANR project to improve the detection of gastric inflammatory lesions and preneoplasia during endoscopy (Bazin et al, 2020, Scientific Rep; 2021, EBioMedicine). Our ongoing project, also developed in collaboration with clinicians, aims to identify circulating candidate biomarkers that will allow an early detection of patients at risk of gastric cancer development.
Key words: gastric cancer, h. pylori, genotoxicity, biomarkers: diagnostic
Patrick Trieu-Cuot / Shaynoor Dramsi
This team works on a medically important gut pathobiont, Streptococcus gallolyticus (previously named S. bovis biotype I), an emerging cause of septicemia and infective endocarditis in the elderly, and whose presence has been strongly linked to the existence of asymptomatic colon neoplasia since the first case report in 1951.
The group recently showed that colorectal cancer specific conditions promote S. gallolyticus gut colonization by a 1,000- fold in the Notch/APC mice and this competitive advantage occurs at the expense of enterococci, a common member of the gut microbiota (Aymeric et al., 2018). Recent promising data indicating that S. gallolyticus can accelerate the development of intestinal tumors in the A/J AOM murine model of CRC (Pasquereau et al., unpublished). They are currently investigating possible mechanisms through transcriptomic, proteomic and histological analyses. In collaboration with the group of Catherine Robbe-Masselot (University of Lille), this team is also studying the impact of S. gallolyticus on the mucus and strong preliminary data indicate that this bacterium is able to alter the expression and glycosylation repertoire of colonic mucins in human HT29 5M21 cells. Interestingly, S. gallolyticus is able to increase mucin sialylation in a similar way to that observed during the development of colorectal cancer (unpublished data).
Key words: streptococcus gallolyticus, s. bovis, colorectal cancer, gut pathobiont, colon
Department of Virology
Pierre Charneau / Yu Wei
Hepatitis B virus infection and liver inflammation in hepatocarcinogenesis
This team main research interests are in host-pathogen interaction during hepatitis B virus (HBV) infection and liver inflammation. HBV infection can cause chronic hepatitis B, which is closely associated with the development of hepatocellular carcinoma (HCC). Inflammation occupies a central position in pathology of liver diseases, including HCC. The team uses cell and mouse models and clinical samples to investigate the role of selective autophagy in HBV infection with a focus on the activities of autophagy receptors. They study the functions of T follicular helper cells (Tfh) and IL-17 in liver inflammation as well as inflammation-associated hepatocarcinogenesis.
Epidemiology of oncogenic viruses (e.g. HHV-8/KSHV and HTLV)
Study of prevalence, genomic diversity, and modes of transmission of oncogenic viruses, throughout the globe (Central Africa, Australo-Melanesia, South America); Study of mechanims of evolution; This team was the first to evidence recombination in HTLV-1;
Study of zoonotic transmission of oncogenic viruses (different molecular genotypes of HTLV-1).
Transmission of the oncoretrovirus HTLV from mother to child (during breastfeeding)
HTLV-1 is the etiological agent of adult T cell leukemia (ATL) a very severe lymphoproliferation. It occurs in individuals infected during childhood. The team thus study the mechanism of viral dissemination across the intestinal barrier, which can occur during long-term breast-feeding from an HTLV-1 infected mother. Moreover, in collaboration with research groups from Institut Necker, APHP and Institut Curie (PI: Vahid Asnafi, Olivier Hermine and Jacques Ghysdael), they are developing a mouse model of xenografts with ATL cells from patients in order to test leukemic mechanisms and the efficiency of new therapeutic approaches.
Alteration of the microenvironment during HTLV-1 infection
Cancer often develops in a favorable, pro-tumoral microenvironment. The team studies the alterations of the microenvironment that occur upon HTLV infection. They have studied the importance of leukotriene B4 in viral propagation, and are now focusing on the importance of extracellular vesicles (exosomes) in oncogenesis.