APRIL 02, 2026, NEW YORK - Tumors driven by cancer-driving KRAS mutations are often susceptible to ferroptosis, a type of cell death that can be harnessed for cancer therapy. Given that more than 95% of pancreatic ductal adenocarcinomas (PDACs) harbor such mutations, one might expect these tumors to be similarly vulnerable. Yet, in keeping with PDAC's notorious intractability, its tumors show no such vulnerability. Why this is so has been something of a mystery.
Researchers led by CEO and Scientific Director of the Ludwig Institute for Cancer Research Chi Van Dang and Maimon Hubbi, a postdoc in his laboratory at Johns Hopkins University, detail in the current issue of Molecular Cell the mechanisms by which salient aspects of PDAC biology converge to counter ferroptosis. Their findings suggest new strategies for the treatment of advanced pancreatic cancer, which carries an overall median life expectancy of less than a year following diagnosis, even with therapy.
"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 tumor microenvironment (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 (hypoxia).
Because high levels of HIF-2 are known to make kidney cancer cells susceptible to compounds that trigger ferroptosis, Hubbi, Dang and their colleagues hypothesized that hypoxic PDAC cells might prove to be similarly vulnerable. To their surprise, cell culture experiments using RSL-3 revealed the opposite to be true.
To explore this effect in conditions that better recapitulate the pancreatic TME, the researchers obtained from Alex Muir's lab at Ludwig Chicago a cell culture medium that mimics the interstitial fluid found between PDAC cells in tumors. They then examined how hypoxic cells in that medium would respond to high doses of erastin.
"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."
The researchers show that HIF-2 coordinates the induction of several anti-ferroptotic measures in PDAC cells. First, it boosts glutathione levels by stepping up expression of the protein transporter that brings the molecule's precursor into the cells, and that of enzymes that help convert them into glutathione. Second, HIF-2 activity promotes mitophagy-the selective breakdown and removal of mitochondria-and reduces mitochondrial production of reactive oxygen species (ROS), thereby limiting the lipid peroxidation that drives ferroptosis.
"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."
The researchers also note that their findings underscore the importance of studying cancer cells within the context of their metabolic environment.
This research was supported by the Ludwig Institute for Cancer Research, the University of Pennsylvania and the U.S. National Institutes of Health.
Aside from his post as CEO and Scientific Director of the Ludwig Institute for Cancer Research, Chi Van Dang is also Bloomberg Distinguished Professor of Cancer Medicine at Johns Hopkins.
