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Metaplasia as an adaptive response to chronic microbial infections

Project description

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.

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.

Host institution

CHRISTIAN-ALBRECHTS-UNIVERSITAET ZU KIEL
Net EU contribution
€ 2 500 000,00
Address
OLSHAUSENSTRASSE 40
24118 Kiel
Germany

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Region
Schleswig-Holstein Schleswig-Holstein Kiel, Kreisfreie Stadt
Activity type
Higher or Secondary Education Establishments
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Total cost
€ 2 500 000,00

Beneficiaries (1)