The effectiveness of most chemotherapeutics is limited by their inability to penetrate deep into
tumor tissue and their ineffectiveness against quiescent cells. Motile Salmonella typhimurium, which are specifically attracted to compounds produced by quiescent
cancer cells, could overcome this therapeutic barrier. We hypothesized that individual chemoreceptors target S. typhimurium to specific tumor microenvironments. To test this hypothesis, we used time-lapse fluorescent microscopy and
tumor cylindroids to quantify the accumulation of chemotaxis machinery knockouts, including strains lacking individual cell surface chemoreceptors, chemotaxis signal transduction pathway
enzymes, and the flagella and motor assemblies. To measure the extent of apoptosis induced by individual bacterial strains,
caspase-3 activity was measured as a function of time. Our results showed how chemoreceptors directed bacterial chemotaxis within cylindroids: the
aspartate receptor initiated chemotaxis toward cylindroids, the
serine receptor initiated penetration, and the
ribose/
galactose receptor directed S. typhimurium toward
necrosis. In addition, strains lacking proper flagella constructs, signal transduction
proteins, or active motor function did not chemotax toward
tumor cylindroids, indicating that directed chemotaxis is necessary to promote accumulation in
tumors. By deleting the
ribose/
galactose receptor, bacterial accumulation localized to
tumor quiescence and had a greater individual effect on inducing apoptosis than wild-type S. typhimurium. This new understanding of the mechanisms of Salmonella migration in
tumors will allow for the development of bacterial
therapies with improved targeting to therapeutically inaccessible regions of
tumors.