Projektbeschreibung
Die Mechanismen bei Formen von Epithelkrebs
Die chronische Infektion der Magenschleimhaut im Zusammenhang mit dem Helicobacter pylori ist ein Beispiel für chronische bakterielle Infektionen, die beim Menschen Epithelkarzinome verursachen können. Obwohl er so häufig auftritt, sind die exakten Mechanismen hinter dem durch Mikroorganismen verursachten Epithelkrebs weiter ungeklärt. Doch jüngste Studien deuten darauf hin, dass die präkanzeröse Phase der intestinalen Metaplasie auf Höhe des Magens ein Weg des Organismus sein könnte, sich adaptiv gegen Mikroorganismen zu wehren. Anhand einer solchen Hypothese will das EU-finanzierte Projekt MADMICS neue Erkenntnisse über die Rolle bakterieller Infektionen bei der Krebsentstehung beim Menschen gewinnen. Darüber hinaus werden Mutationen und Veränderungen der Epigenetik im Zusammenhang mit der intestinalen Metaplasie sowie neue Präventionsmöglichkeiten gegen Krebs erforscht.
Ziel
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.
Wissenschaftliches Gebiet
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-ADG - Advanced GrantGastgebende Einrichtung
24118 Kiel
Deutschland