Researchers at Johns Hopkins Kimmel Cancer Center have identified how a common gut bacterium triggers colon cancer. The team, led by Cynthia Sears, M.D., discovered that a bacterial toxin called BFT attaches to a protein called claudin-4 on intestinal cells, allowing it to damage the colon's protective lining and promote tumor growth.
For nearly two decades, scientists knew that Bacteroides fragilis, found in the intestines of up to 20% of healthy people, could produce BFT and damage colon tissue. But the mechanism of attachment remained unknown. The toxin damages E-cadherin, a protein that holds intestinal cells together, but researchers could not explain how BFT first reached its target.
Maxwell White, an M.D./Ph.D. candidate in Sears' laboratory, used CRISPR gene-editing technology to systematically disable genes in colon cells. When researchers disabled the gene for claudin-4, BFT could no longer bind to cells or attack E-cadherin. Collaborators at the Molecular Biology Institute of Barcelona, including F. Xavier Gomis-Rüth and Ulrich Eckhard, confirmed that BFT and claudin-4 form a tightly bound complex in laboratory experiments.
The discovery was unexpected. Researchers had predicted the toxin would interact with a signaling receptor, not a structural protein that maintains cell-to-cell connections. The team also could not identify another bacterial toxin using this same mechanism.
Using this finding, White and colleagues at Harvard Medical School, working with Min Dong's laboratory, developed a molecular decoy carrying claudin-4 sequences. In mice, the decoy successfully intercepted BFT before it could damage colon cells. The results appear in Nature. The research received partial support from the National Institutes of Health.
White said the team is now exploring which molecular approaches might most successfully block the toxin, including small molecules or other biologics with better pharmacological properties.