Maintaining health of an organism involves protecting its genome from harmful environmental influences. One such protective mechanism is by the tumor suppressor protein p53, also referred to as the "guardian of the genome". This protein is in the focus of our research as its coding gene TP53 represents one of the most frequently mutated genes in cancer and often stands at the beginning of the mutational cascade of carcinogenesis. Our interest in p53 is twofold; (a) in technical terms: As a highly effective tumor suppressor, p53 can drive cells into apoptosis once they experience double-strand breaks (DSB). DSBs, however, are experimentally generated during CRISPR/Cas9-based mutagenesis. Since adult human stem cells appear to be particularly sensitive to the action of p53, it is difficult to mutate these cells. Moreover, once TP53 mutations are generated, the cells tend to become unstable, which complicates experimental analysis. And (b) in scientific terms: we are interested in our observation that mutant p53 cells exhibit an antibacterial property, which may explain the observed elimination of H. pylori from the gastric mucosa in GIM. The p53 tumor suppressor thus exemplifies the dual function of certain mutational events, collectively referred to ‘adaptive antimicrobial mutations’ (ADAMs) that link the initiation of tumorigenesis and genetic immunity against pathogen infections.
To explore this intricate functional duality of ADAMs in tumor progression and pathogen defense, we have used native human primary cells in the form of so-called organoids. These highly authentic human experimental models constitute an ideal tool for studying the early events of human carcinogenesis. In many respects, organoids are superior to animal models and also to the cell lines used so far, which are mostly derived from tumor tissue, which is the endpoint of our experimental approach and therefore provide an uncertain basis of valid results. The use of organoids, however, will provide us with the anticipated insight in the evolutionary context of, and the link between genetic immunity and premalignancy.
In addition to the characterization of ADAMs, MADMICs also addresses the specific mutational processes that are the cause ADAMs and mutant p53 (mutp53), as well as the competitive features of normal versus mutant cells which ultimately determine the emergence of a cancer lineage in the tissue context.
