The Type of Fat—Not the Amount—Fuels Pancreatic Cancer

For decades, the relationship between fat and cancer has been treated as a question of quantity: eat less fat, reduce your risk of developing cancer.

The research, published April 29 in Cancer Discovery, a journal of the American Association for Cancer Research, shows that for pancreatic cancer, the type of fat you consume matters more than the amount.

"It's really the type of fat that you're consuming, not just total fat content," says Christian Felipe Ruiz, PhD, an associate research scientist in Yale School of Medicine's Department of Genetics and lead author of the study. "Depending on the type of fat that you consume, it can go completely different ways. We found that some fats promote cancer, as we would expect, while other fats are really good at suppressing cancer."

One fat in particular—oleic acid, the primary fatty acid in olive oil—may be accelerating tumor growth in ways scientists never anticipated. The result was surprising given oleic acid's reputation in medicine. "It's traditionally been considered a healthy type of fat for cardiovascular health," Ruiz says.

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers. Only about 13% of patients diagnosed with PDAC survive five years. "More than 65,000 people are expected to be diagnosed with PDAC in the U.S. this year, with over 50,000 deaths,” Ruiz notes. “At the moment, effective treatment options are limited, especially for advanced disease. Therefore, prevention strategies are sorely needed to move the needle on PDAC mortality."

High-fat diets have long been associated with increased PDAC risk, but the precise biological mechanisms have not been pinned down. The new study, led by senior author Mandar Deepak Muzumdar, MD, associate professor of genetics and of internal medicine at YSM, takes direct aim at that gap.

Muzumdar is also a member of Yale Cancer Center and the Yale Cancer Biology Institute at West Campus.

To find out the effects of each fat, Ruiz and colleagues designed a comprehensive dietary screen using 12 high-fat diets, each identical in caloric content but differing solely in fat source. The diets were modeled on real patterns of modern American fat consumption.

Ruiz says that, for decades, the research community broadly “gave mice very high levels of fat in their diet, often using a single fat source.” Most prior studies used lard-based diets at 60% fat by calories—a formulation that neither reflects what most people actually eat nor isolates the effects of specific fatty acids.

“Exactly what components of dietary fat cause cancer has remained a mystery,” Ruiz adds.

What the team found was striking. Diets rich in oleic acid—a monounsaturated fatty acid (MUFA) found in, among other foods, olive oil, high-oleic safflower oil, high-oleic sunflower oil, peanuts, and lard—significantly accelerated tumor development in mice carrying a genetic mutation that leads to illness closely mimicking human PDAC development. However, diets high in polyunsaturated fatty acids (PUFAs) suppressed it, especially omega-3 fatty acids, such as those found in fish oil.

"When we fed mice diets enriched with fish oil, we saw a 50% reduction in disease compared with mice fed a standard fat diet."

These findings prompted the team to explore ferroptosis, a form of programmed cell death triggered by lipid oxidation. When fatty acids are incorporated into pancreatic cell membranes, their chemical properties determine how vulnerable those cells are to oxidative damage. PUFAs oxidize readily, which makes cancer cells susceptible to ferroptosis and cell death. MUFAs resist oxidation, shielding cancer cells from that fate.

"Monounsaturated fats really protect the cancer cells from lipid oxidation," Ruiz explains. "Because oxidation is reduced, they're less likely to undergo ferroptosis." The effect on tumor development was direct and measurable. "When we increased the ratio of MUFAs to PUFAs in the diet, disease burden increased. Conversely, when we decreased the ratio, disease burden was reduced."

The study also found sex-based differences: The tumor-promoting effects of oleic acid were significant in male mice but largely absent in females. In contrast, dietary PUFAs suppressed cancer development in both sexes. Ruiz notes that these findings contribute to a growing recognition that sex can influence metabolic regulation of tumor development and highlight the need for further study in this area.

Though the study has not been replicated in humans, the clinical implications could be most immediate for high-risk groups: people with chronic pancreatitis, a family history of pancreatic cancer, late-onset diabetes, or obesity.

"One of the most common questions clinicians get is ‘What can I change in my diet to prevent cancer?’" Ruiz says. "Right now, we don’t have clear answers, but this study begins to shed light on how we might address that question."

Ruiz says the next step is determining whether dietary fat composition can improve outcomes in patients with established tumors and whether the ratio of MUFAs to PUFAs in blood could serve as an early biomarker for pancreatic cancer risk.