Cancers of the gallbladder and bile ducts are among the deadliest human cancers, with fewer than one in ten patients surviving five years. Most of these deaths come from metastasis, the spread of cancer cells to other organs. These cancers are also closely tied to a bacterial infection: people who carry the bacterium that causes typhoid fever for many years have nearly five times the risk of gallbladder cancer, one of the strongest infection- cancer links known. Yet no suitable laboratory model exists for studying how the bacterium drives these cancer cells to spread, or for testing which treatments are most likely to work. Our early results point to one bacterial product as the culprit: typhoid toxin, which damages DNA inside cells. Cancer cells taken from mouse tumors exposed to toxin-producing bacteria became far more invasive than cells exposed to bacteria engineered to lack the toxin. The toxin appears to act as an “on-switch” for aggressive, invasive behavior. This one-year project will build that missing model of bacterial genotoxin-driven metastasis. We will transplant human gallbladder cancer cells into mice, expose the tumors to the bacterium or purified toxin, and measure how invasive the cancer cells become. We will also determine which of the toxin’s two entry routes operates in human cells. This is the principal investigator’s first cancer-focused project, matching the Bass Endowment’s priority for faculty new to cancer research. Overall, this work will advance our understanding of infection-related cancer biology and help identify better therapies for patients.