Engineered Lactiplantibacillus plantarum WCFS1 as a Biosensor Probe for Lung Cancer

Lung cancer is exceedingly difficult and costly to detect early, leading to delayed diagnosis, limited treatment options, and high patient mortality. Tumor-secreted molecules are useful in identifying early disease but are difficult to detect when diluted in accessible bodily fluids. Here, we demonstrate a low-cost, minimally invasive method to probe the lungs for disease using genetically engineered Lactiplantibacillus plantarum bacteria as living biosensors. When delivered to the lungs of mice, the engineered bacteria remained transcriptionally active for several hours and were cleared without colonization. Nanoluciferase secreted by bacteria from within the lungs was subsequently detected in mouse urine. Bacteria were engineered to secrete nanoluciferase in response to a model peptide excreted by a mouse lung cancer cell line, allowing the bacteria to detect tumors formed from these cells in the lungs of mice. Finally, biosensor bacteria were also able to detect a secreted protease overexpressed in adenocarcinoma using a probe protein that is cleaved to release a bacterial pheromone peptide. These results indicate that genetically engineered commensal bacteria yield tremendous promise as living biosensors for early detection screens of lung cancer.