Descripción del proyecto
Un estudio más detallado de los mecanismos de las neoplasias malignas de origen epitelial
La infección gástrica crónica relacionada con «Helicobacter pylori» es un ejemplo de cómo una infección bacteriana crónica puede inducir neoplasias malignas de origen epitelial, o carcinomas. A pesar de ser frecuente, los mecanismos exactos de este tipo de neoplasias inducidas por microbios siguen sin conocerse. Sin embargo, investigaciones recientes sugieren que la fase precancerosa de la metaplasia gastrointestinal podría ser una forma de defensa adaptativa antimicrobiana de un organismo. El proyecto MADMICS, financiado con fondos europeos, investigará esta hipótesis para arrojar luz sobre el papel de las infecciones bacterianas en el desarrollo de las neoplasias malignas. El proyecto también estudiará los cambios mutacionales y epigenéticos relacionados con la metaplasia gastrointestinal, así como una nueva forma de prevención del cáncer.
Objetivo
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.
Ámbito científico
Programa(s)
Régimen de financiación
ERC-ADG - Advanced GrantInstitución de acogida
24118 Kiel
Alemania