Intracellular bacteria enable pancreatic cancer cells to survive nutrient stress

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with a 5-year survival rate of less than 10%. PDAC cells exhibit the extraordinary ability to survive a nutrient-poor and hypoxic microenvironment. To do so, PDAC cells reprogram metabolism and become highly dependent on glutamine, a non-essential amino acid, for survival. Bacteria are present in human tumors and are mostly intracellular in both cancer and immune cells. The role of intracellular organisms in tumor progression is not clear. Porphyromonas gingivalis (PG), an assacharolytic, Gram-negative anaerobic bacterium associated with periodontal disease, is linked in epidemiological studies to increased risk for pancreatic cancer. We previously showed that PG can survive intracellularly and promote the proliferation of PDAC cell lines. We now demonstrate that intracellular bacteria enable pancreatic cancer cells to survive in nutrient starvation. Intracellular PG mitigated the increased reactive oxygen species production of cells cultured in the absence of glucose, but not in the absence of glutamine. Furthermore, intracellular PG enabled PDAC cells to survive nutrient stress conditions that otherwise lead to complete cell death. PG increased host cell expression of enzymes associated with non-canonical glutamine metabolism. This metabolic shift enhanced the anti-oxidative capacity of PDAC cells through increased reduced glutathione levels. These findings suggest that tumor cell intracellular bacteria can promote growth and survival via metabolic reprogramming.