Studying the potential of mutations induced by microbial genotoxins to induce colorectal cancer

Objective

The increasing incidence of early-onset colorectal cancer (EO-CRC) points to an unknown, possibly preventable, cause. A strong candidate is the gut microbiome. Experimental studies show certain bacterial strains can affect CRC onset, potentially by producing genotoxins that induce cancer-driving mutations. Our project aims to test this hypothesis. We have identified colibactin, a genotoxin produced by certain E. coli strains, which leaves a specific mutation pattern (SBS88) found in both healthy colon cells and in about 12% of CRC tumors. Another similar mutation pattern, SBS89, also appears to be acquired early in life, but its cause is unknown. Our two main objectives are to: Identify mutational patterns induced by microbial genotoxins by systematically screening them in human intestinal organoids and comparing the results to large cancer databases. Secondly, we aim to determine the role of these mutations in driving cancer by performing transformation screens in organoids, identifying how genotoxins can initiate cancer and lead to mutations in key driver genes. This research will help explain rising EO-CRC rates, identify individuals at risk, and guide future preventive strategies. Our team has extensive expertise in organoid research, genomic analysis, and the study of colibactin-induced mutations, making us uniquely qualified to address this critical public health issue.