Description du projet
Un regard plus attentif sur les mécanismes des cancers des tissus épithéliaux
L’infection gastrique chronique liée à Helicobacter pylori est un exemple de la manière dont une infection bactérienne chronique peut induire des cancers humains du tissu épithélial. Malgré son occurrence fréquente, les mécanismes exacts du cancer épithélial induit par les microbes restent inexpliqués. Cependant, de récentes recherches suggèrent que la phase précancéreuse de la métaplasie intestinale gastrique (MIG) pourrait constituer une forme de défense adaptative antimicrobienne d’un organisme. Le projet MADMICS, financé par l’UE, étudiera cette hypothèse afin d’apporter un éclairage nouveau sur le rôle des infections bactériennes dans le développement du cancer chez l’homme. Il recherchera également les changements mutationnels et épigénétiques liés à la MIG, ainsi que de nouveaux moyens de prévention du cancer.
Objectif
The epithelial surfaces are frequently affected by harsh encounters, thus it is not surprising that most cancers originate here. Several chronic bacterial infections have been implicated in human cancers, with Helicobacter pylori (Hp) representing the paradigm of a cancer-inducing bacterium. The gastric pathology of infection tends to progress from mild symptoms, via active gastritis, atrophy, gastric intestinal metaplasia (GIM) and dysplasia towards gastric adenocarcinoma. Intriguingly, GIM is usually cleared of Hp, suggesting this pathological state is not merely an intermediate stage towards cancer development, but can be viewed as a process of adaptive defence.
Mutations in the tumor suppressor gene TP53 are frequent events of epithelial malignancy in numerous tissues. Based on compelling evidence from an analysis of congenic mutant organoids and related observations, I pursue the hypothesis that pre-malignant mutations in the epithelium arise as an adaptive response to persistent infections and thus constitute a novel layer of antimicrobial defence and tissue protection. MADMICs will have its main focus on the mutational and epigenetic changes associated with GIM and also touch comparable mucosal pathologies investigated by the PI in recent years. An apparent hallmark of such persistent bacterial infections and related cancers is their link to the function of tumor suppressor p53.
MADMICs will capitalize on the PI’s profound experience with pathogens, primary cell culture and chronic infection models. Organoids from normal and premalignant human tissues and isogenic mutant organoids created via CRISPR/Cas9 will be used to explore host cell signaling and mutator pathways with regard to early cancer mutations and their antimicrobial effects. The study will illuminate an unprecedented mechanism of microbial defence from a number of perspectives and likely lead to a paradigm shift of our view on the link between adaptive host responses and early cancer mutations.
Champ scientifique
Programme(s)
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Régime de financement
ERC-ADG - Advanced GrantInstitution d’accueil
24118 Kiel
Allemagne