Researchers led by Chi Van Dang, CEO and Scientific Director of the Ludwig Institute for Cancer Research, and Maimon Hubbi, a postdoctoral researcher at Johns Hopkins University, reported on Apr. 2 that pancreatic ductal adenocarcinomas (PDACs) resist ferroptosis despite having KRAS mutations that typically make tumors vulnerable to this form of cell death.
This discovery is significant because more than 95% of PDACs carry KRAS mutations. Ferroptosis is a type of cell death driven by iron-dependent lipid oxidation and has been explored as a potential therapeutic strategy against cancer. However, PDAC remains one of the most difficult cancers to treat, with patients facing a median life expectancy of less than a year after diagnosis even with therapy.
Hubbi said, "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." He continued, "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."
The study describes how HIF-2 helps PDAC cells survive by increasing glutathione levels through enhanced expression of transporters and enzymes involved in its production. It also promotes mitophagy—removal of mitochondria—and reduces mitochondrial production of reactive oxygen species (ROS), limiting lipid peroxidation associated with ferroptosis. Experiments showed that when hypoxic conditions were combined with nutrient profiles similar to those found around actual tumors, resistance was even stronger.
Dang said, "Our findings highlight how extensively the tumor microenvironment shapes the susceptibility of cancer cells to death." He added that targeting specific biochemical pathways activated by HIF-2 could potentially make pancreatic tumors more sensitive to therapies based on inducing ferroptosis.
The researchers emphasized the importance of studying cancer within its metabolic environment for developing effective treatments. The research received support from the Ludwig Institute for Cancer Research, University of Pennsylvania, and U.S. National Institutes of Health.
