Research Snapshot: UF researchers shed light on role of bacterial metabolite in colorectal cancer mutations

A new study by University of Florida Health Cancer Center researchers helps explain how a metabolite in some gut E. coli drives genetic mutations involved in colorectal cancer. The study, published recently in the journal Neoplasia, suggests that colibactin may exacerbate mutations associated with colorectal cancer and could have important implications for assessing the role of the gut microbiome in colorectal cancer in humans.

For the first time, the study establishes a link between colibactin’s proposed DNA-binding mechanism and subsequent development of mutations.

Led by Michael Dougherty, a graduate student in the lab of Christian Jobin, Ph.D., the study focused on colibactin, a metabolite found in some E. coli in the intestinal microbiome. In preclinical models, colibactin-producing E. coli have been found to promote colorectal cancer. Laboratory testing has found these E. coli induce a specific mutational signature also found in human colorectal cancer genomes.

In the new study, the researchers found that colorectal cancer tumors driven by colibactin-producing E. Coli in mice had a significantly higher burden of genetic mutations than tumors with colibactin-deficient E. coli. A larger percentage of these mutations was attributed to a signature associated with mismatch repair deficiency, a genetic mutation associated with colorectal cancer.

To attribute the development of mutations directly to colibactin, the researchers then tested synthetic colibactin homologs in mismatch repair-deficient human colorectal cancer cells. They found that repeated exposure similarly increased the number of mutations attributed to mismatch repair deficiency.

The findings shed light on the host response mechanisms underlying colibactin-associated DNA damage. The study also raises the question of whether patients with mismatch repair deficiency may be at higher risk of colorectal cancer after infection with E. coli involving colibactin, but further testing with natural colibactin is required to determine the translational relevance of the findings, the researchers said.

Prior studies have demonstrated that colibactin exposure promotes a canonical signature. However, the observation that pks bacteria, which produce colibactin, may exacerbate mutations associated with mismatch repair suggests that mutations driven by pks+ E. coli may be a greater risk factor in colorectal cancer than was previously known.

By using novel synthetic colibactins, along with identical molecules with structural changes to proposed DNA-binding residues, the researchers underscored the significance of the findings. For the first time, the study establishes a link between colibactin’s proposed DNA-binding mechanism and subsequent development of mutations.

Because the molecule itself degrades rapidly and cannot be isolated, the study provides a better mechanistic understanding that can be used to develop therapeutic interventions aimed at reducing the genotoxicity of colibactin or commercial applications developing colibactin as a potential chemotherapeutic drug, the researchers said.

Jobin, a professor in the division of gastroenterology in the UF College of Medicine, is co-leader of the UF Health Cancer Center’s Cancer Therapeutics and Host Response research program. Other co-authors from the UF Health Cancer Center are Raad Gharaibeh, Ph.D., Jason Brant, M.D., and Alberto Riva, Ph.D.

The study was funded by the National Cancer Institute, the UF Health Cancer Center and the UF Department of Medicine Gatorade Fund.

Read the study in Neoplasia.

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