PDAC Resistance to Ferroptosis Explained

Tumors with KRAS mutations typically prove vulnerable to ferroptosis, an iron-dependent cell death process that can be harnessed for cancer therapy. Over 95% of pancreatic ductal adenocarcinomas (PDACs) carry these mutations, yet their tumors resist ferroptosis despite this predisposition. Researchers led by Chi Van Dang of the Ludwig Institute for Cancer Research and Maimon Hubbi from his Johns Hopkins University lab explain this resistance in a Molecular Cell study. Their work identifies mechanisms driven by PDAC's tumor microenvironment (TME) that could inform new treatments for this cancer.

"Our findings reveal that two defining features of the pancreatic tumor microenvironment—the composition of metabolites in the fluid around PDAC cells and severe oxygen deficiency, or hypoxia—cooperate to induce resistance to ferroptosis," said Hubbi. "We've identified the hypoxia-inducible factor-2 (HIF-2), a cellular sensor of oxygen starvation that is highly active in PDAC cells, as a critical mediator of this effect and detailed the mechanisms it triggers in PDAC cells to suppress ferroptosis."

Driven by a rapidly expanding, iron-driven oxidation of the lipid molecules that build cell membranes, ferroptosis culminates in membrane disintegration and cell death. To forestall this cascading reaction, cells depend on a molecule known as glutathione, an antioxidant used by an enzyme named GPX4 to convert oxidized lipids into a less pernicious species of molecules. A pair of compounds that induce ferroptosis in cells sporting KRAS mutations—erastin and RSL-3—have been found, respectively, to block the import of molecules from which glutathione is manufactured or inhibit GPX4 activity.

Pancreatic tumors are encased in a virtually impenetrable sheath of fibrous tissue and have far fewer blood vessels than almost any other type of tumor—two of the many characteristics that contribute to their stubborn resistance to therapy. The low blood supply also leaves their TME starved of oxygen. To cope, PDAC cells express high levels of HIF-2, whose primary function is to manage a sweeping program of gene expression by which cells adapt to oxygen deprivation.

Cell culture tests with RSL-3 under hypoxia surprised the team, showing PDAC resistance. Using a PDAC TME-mimicking medium from Alex Muir's Ludwig Chicago lab, they tested erastin on hypoxic cells. "The result was even more striking when hypoxic cells were grown in this medium," said Hubbi. "The combination of hypoxia and the nutrient profile of PDAC interstitial fluid almost completely protected PDAC cells from ferroptosis."

HIF-2 activates multiple defenses: it upregulates transporters and enzymes for glutathione production while promoting mitophagy to curb mitochondrial reactive oxygen species (ROS) and lipid peroxidation. These adaptations shield PDAC cells from ferroptotic damage. 

"Our findings highlight how extensively the tumor microenvironment shapes the susceptibility of cancer cells to death," said Dang. "They explain why PDAC is so resistant to ferroptosis and suggest that targeting specific intracellular biochemical pathways activated by HIF-2 could sensitize pancreatic tumors to ferroptotic therapies."