A 3-4years PhD position is available in 2021-2022 at the University of Bordeaux – INSERM Unit UMR1053 BaRITOn, Bordeaux Research In Transational Oncology – Team 2 – FRANCE.

Microbiota and cancer: study of the role of bacterial genotoxins in digestive carcinogenesis 

Humans are frequently infected with genotoxin-producing bacteria, CDT (for “cytolethal distending toxin”) and colibactin. These toxins damage the DNA of host cells and are a predisposing factor for the development of cancer. The demonstration of the role of the CDT of Helicobacter hepaticus in inflammation and development of hepatic carcinogenesis in mice, makes this toxin a relevant candidate in the activation of precancerous processes. CDT toxin is widespread in many mucosal pathogens involved in diseases. CDT, via the DNA damage it induces, increases the frequency of mutation, base additions/deletions and chromosomal aberrations in the human genome; it promotes chromatin accumulation and genomic instability. It is therefore a relevant candidate in the activation of pro-cancerous processes. We have shown the formation of transient nuclear invaginations, rich in ribonucleoprotein particles, in cells surviving CDT-induced DNA damage. We also performed a transcriptomic study and showed that CDT induces a Th17-type inflammatory response as well as an antimicrobial signature in vitro. This study also showed the regulation of genes associated with cancer (unpublished data) such as the MAFB oncoprotein. In addition, we have shown that CDT induces major remodeling of the cell cytoskeleton, the formation of actin stress fibers and the loss of vinculin from focal adhesion plaques. CDT also induces protrusion of large lamellipodia and a decrease in cell adhesion. These phenotypes are similar to those induced during epithelial-mesenchymal transition (EMT), a process in which cells lose their epithelial characteristics in favor of mesenchymal characteristics conducive to cell motility. EMT plays an important role in all stages of cancer.

The objective of the thesis is to study the role of CDT in digestive carcinogenesis. The transcriptome data will be used to study the EMT- and cancer-associated genes regulated by CDT. The phenotypes associated with cancer will also be studied in response to CDT. The effect of CDT on the expression of epithelial and mesenchymal markers, the integrity of cell junctions, cell migration and motility will be studied in different models in vitro and in vivo. We will use the different models set up in the laboratory such as 1) coculture experiments of cells infected with wild-type and CDT-mutated strains, 2) models of transgenic lines expressing the toxin and its catalytic mutant and 3) infection of mouse livers with Helicobacter hepaticus. 

Colibactin, cytolethal distending toxin B, cancer, DNA damage, cell survival, epithelial–mesenchymal transition 

The involvement of chronic bacterial infections in carcinogenesis has been demonstrated for Helicobacter pylori, a bacterium classified as carcinogenic since 1994 by the WHO and associated with the development of 2 digestive cancers in humans. Since then, some Helicobacter, such as H. pullorum, have been associated with human digestive pathologies such as hepatocellular carcinoma. Another Helicobacter, H. hepaticus, colonizes the mouse intestine, then the bile ducts and the liver, where it induces inflammatory lesions, hepatitis and, in some older animals, hepatocarcinoma. It has also recently been shown that H. hepaticus induces intestinal lesions and colonic tumorigenesis in mice. Thus, H. hepaticus constitutes an excellent model for the study of carcinogenesis processes.

The H. hepaticus genotoxin Cytolethal Distending Toxin (CDT), via its CdtB subunit, plays a major role in inflammation and the development of hepatic carcinogenesis, suggesting that, like the proinflammatory protein CagA of H. pylori, this toxin would have an oncogenic power. CDT is secreted by many mucosal pathogens. It is composed of 3 subunits and induces, via its CdtB subunit (phosphatidylinositol 3,4,5 triphosphate phosphatase and DNase activities) double-strand breaks of DNA thus triggering a repair point comparable to that induced by ionizing radiation. Improper repair of these breaks can lead to base additions / deletions, or even chromosomal rearrangements, causing cancer. Thus, chronic exposure to CDT of Gram-negative bacteria alters the response to DNA damage in different cells, promotes genomic instability and the acquisition of phenotypic properties of malignancy. Although CDT is widely distributed in many gram-pathogenic bacteria, it remains little studied (426 publications) due to its high toxicity and the difficulties relating to its production / penetration into target cells.

The material and methods have been developed in the laboratory: available transcriptomis data in response to CDT intoxication, bacteria/cell cocultures models, hepatic and intestinal transgenic lines expressing the wild-type and mutated toxin in its catalytic site, livers of mice infected with Helicobacter hepaticus.

The student will be supervised by a study engineer and Armelle Ménard. The techniques will be taught by laboratory personnel competent in the field. The progress of the work will be checked weekly. Results will be regularly presented and discussed with the members of the group, team and during lab meetings. The student will present his work at French congresses. Each PhD student in the laboratory takes part in at least one international congress (with some exceptions).

The results of the research study will be presented through oral communications and / or displayed during national and international meetings, conferences and congresses. The student who carried out the work is the first author of the publications resulting from his work. The thesis work will be carried out within team 2 of UMR INSERM 1053 BaRITOn – Bordeaux Research in Translational Oncology located on the Carreire campus of the University of Bordeaux. (https://bariton.u-bordeaux.fr/) The National Reference Center for Helicobacter and Campylobacter located in the Bordeaux University Hospital actively participates in all research projects concerning Helicobacters and Campylobacters.

● Must hold a Master’s degree or a current PhD student

● Knowledge of bacteriology, cellular signaling and cancer

● Good knowledge of cellular signaling is preferred

● Experiments must be carried out in type 2 laboratories and type 2 animal quarters

● Can speak French

● Fluency in spoken and written English

● Strong interpersonal and English communicative skills

● Proficiency in MS software (e.g. Word, Excel, Power point)