Metabolic engineering of probiotic Escherichia coli for cytolytic therapy of tumors

Bacterial cancer therapy was developed using probiotic Escherichia coli Nissle 1917 (EcN) for medical intervention of colorectal cancer. EcN was armed with HIyE, a small cytotoxic protein, under the control of the ara BAD promoter (P-BAD). The intrinsic limitation of P-BAD for the gene expression is known to be negated by glucose and afflicted with all-or-nothing induction in host bacteria. This issue was addressed by metabolic engineering of EcN to uncouple the glucose-mediated control circuit and the L-arabinose transport-induction loop and to block L-arabinose catabolism. As a result, the reprogrammed strain (designated EcNe) enabled efficient expression of HIyE in a temporal control manner. The HIyE production was insensitive to glucose and reached a saturated level in response to L-arabinose at 30-50 mu M. Moreover, the administrated EcNe exhibited tumor-specific colonization with the tumor-to-organ ratio of 10(6):1. Equipped with HIyE, EcNe significantly caused tumor regression in mice xenografted with human colorectal cancer cells. Overall, this study proposes a new strategy for the bacteria-mediated delivery of therapeutic proteins to tumors.

Automated summary

This study developed a new strategy for the bacteria-mediated delivery of therapeutic proteins to tumors by reprogramming Escherichia coli Nissle 1917 to express HIyE efficiently. The engineered strain EcNe showed great potential in tumor therapy and tumor regression.