In the hunt for causes of colorectal cancer, scientists have long eyed the scores of bacteria that live in our intestinal tract as possible culprits. For example, researchers have found that contact between bacteria and gut cells seems to propagate tumor formation, and some gut cells that have become cancerous contain certain bacterial molecules. But mechanistic details of how the bacteria could trigger a malignant transformation have been hard to pin down.
New research provides some of that detail. A toxin secreted by Escherichia coli can damage the genomes of cells lining the intestines by alkylating their DNA. If these cells don’t repair this damage precisely, the resulting changes to DNA could push a cell toward cancer, says Emily Balskus, the Harvard University chemist who led the research along with University of Minnesota chemist Silvia Balbo (Science 2019, DOI: 10.1126/science.aar7785).
Figuring out the chemical interaction between the toxin and DNA is an important advance for the field, says chemical biologist Jason Crawford of Yale University, who also studies the relationship between intestinal bacteria and cancer. “The problem we are trying to solve is, How does bacteria regulate colorectal cancer?” Crawford says. “If you can understand that, you can develop strategies to prevent it.”
The toxin is called colibactin, and it joins a group of cyclopropane-containing molecules known to alkylate DNA and form structures called adducts.To find these adducts, the research team used a novel mass spectrometric method developed by Balbo that specifically spots changes in DNA. After testing the method in colon cells grown in culture, the team looked at the colons of mice colonized by just E. coli that produce colibactin. They identified structures indicating that DNA adducts formed through a reaction between a nitrogen on the ring of the DNA base adenine and colibactin’s cyclopropane ring. Their mass-spec data suggest that another reaction occurs between DNA and another part of colibactin to yield a thiazole ring, but Balskus says they are still trying to figure out what is happening.
Balskus says they also need to connect the dots from colibactin-alkylated DNA to cancer. Scientists have studied the mechanisms of some older chemotherapeutic agents and tobacco carcinogens that react similarly with DNA. In those cases, the alkylated base falls off the DNA strand, alerting DNA repair machinery, which either struggles to fix the gap or replaces it with the wrong base. This mutation induces tumor formation or disrupts some process that suppresses tumor formation.
Crawford says one interesting question is, What DNA sequence around an adenine allows colibactin to bind and react? That information could help researchers understand which adenines are at the highest risk of being alkylated. His team is working on anticolibactin compounds, including one made by E. coli to protect itself from the toxin’s DNA-shredding power.
Meanwhile, Balskus thinks that these adducts could serve as a biomarker for colorectal cancer development, perhaps as part of diagnostic screens. It would be a fairly new breed of biomarker, but it would indicate a type of DNA damage that might happen early in tumor development.