Project description DEENESFRITPL A closer look at mechanisms of epithelial tissue cancers Chronic gastric infection related to helicobacter pylori is an example of how chronic bacterial infection can induce human cancers of epithelial tissue. Despite its frequent occurrence, the exact mechanisms of microbe-induced epithelial cancer remain unexplained. However, recent research suggests that the precancerous phase of gastric intestinal metaplasia (GIM) could be a form of an organism’s antimicrobial adaptive defence. The EU-funded MADMICS project will investigate this hypothesis to bring new light to the role of bacterial infections in human cancer development. The project will also look at mutational and epigenetic changes connected to GIM as well as a new means of cancer prevention. Show the project objective Hide the project objective Objective 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. Fields of science medical and health sciencesclinical medicineoncologyprostate cancernatural sciencesbiological sciencescell biologycell signalingnatural sciencesbiological sciencesmicrobiologybacteriologynatural sciencesbiological sciencesgeneticsmutationmedical and health sciencesbasic medicinepathology Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-2019-ADG - ERC Advanced Grant Call for proposal ERC-2019-ADG See other projects for this call Funding Scheme ERC-ADG - Advanced Grant Host institution CHRISTIAN-ALBRECHTS-UNIVERSITAET ZU KIEL Net EU contribution € 2 500 000,00 Address OLSHAUSENSTRASSE 40 24118 Kiel Germany See on map Region Schleswig-Holstein Schleswig-Holstein Kiel, Kreisfreie Stadt Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 2 500 000,00 Beneficiaries (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all CHRISTIAN-ALBRECHTS-UNIVERSITAET ZU KIEL Germany Net EU contribution € 2 500 000,00 Address OLSHAUSENSTRASSE 40 24118 Kiel See on map Region Schleswig-Holstein Schleswig-Holstein Kiel, Kreisfreie Stadt Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 2 500 000,00