Cytosolic transport of citrate protects pancreatic cancer from ferroptosis under nutrient stress.
Pancreatic cancer is a deadly disease as the long-term overall survival rate is only 12%, indicating that there is no effective therapeutic approach available to the patients. Recent studies link the conditions in the pancreatic tumor microenvironment to the aggressive phenotype of the disease and drug resistance. The pancreatic tumor microenvironment is poorly perfused, which limits the nutrients and oxygen availability for tumor cells. We and others have demonstrated that cancer cells rewire their metabolism to adapt to harsh conditions present in the tumor microenvironment of pancreatic cancer. A better understanding of metabolic dependencies may assist in developing targeted therapies. Our results demonstrate that cytosolic transport of citrate via a transporter, SLC25A1, confers a survival advantage to pancreatic cancer cells by protecting them against ferroptosis, an iron-dependent cell death mechanism, under nutrient withdrawal. Additionally, targeting the transporter via a small molecule inhibitor of SLC25A1 prevents the growth of subcutaneous pancreatic xenograft tumors in animals. Any therapeutic advance in the area of pancreatic cancer beyond conventional chemotherapy would significantly improve lives and outcomes. Overall design: RNA-seq profiling of SLC25A1, ACLY, and ACO1 gene knock-down in MiaPaCa-2 cells.