Stress granules may cause obesity-associated pancreatic cancer

Obesity is a known risk factor for at least 13 cancers, in part because it causes an ever-present inflammatory condition. For years, a researcher wondered if the story is nothing more than inflammation. New research from Dr. Elda Grabocka shows a new way in which obesity can stimulate cancer formation in pancreatic cancer, with a five-year survival rate of 11% for the majority of patients. In a study published in Cancer Discovery, the researchers found that stress granules were much more common in obesity-related pancreatic cancer compared to non-obese patients, and most importantly, blocking their formation stopped cancer growth in animals. The research reveals a new direction for cancer therapy development.

“Research on stress beads is exploding right now, but there’s still a lot we don’t know about what they’re made of and how they work,” says Dr. Grabocka, a researcher at the Sidney Kimmel Cancer Center – Jefferson Health and an assistant professor at Thomas Jefferson University. “This work is the first to show that an overload of stress granules enables tumor growth in the pancreas. Our experiments in mice also showed a complete reversal of cancer growth in the lab.”

Stress granules are an unusual type of cell compartment. The cell generates these membraneless organelles in response to stress and to protect the cell from stress-induced self-destruction. It is a cellular reflex and defense mechanism present in the animal and plant kingdoms. Even tomato plants produce stress granules to protect their cells. Researchers still don’t know what these organelles are made of and how exactly they protect the cell. However, it is clear that cancers have co-opted this defense mechanism to their own advantage. Many cancers produce much higher levels of stress granules than normal cells, to help protect the cancer cells from triggering a natural self-destruct sequence.

Knowing this, Dr. Grabocka a mouse model of cancer that blocked the formation of stress granules in pancreatic cancer in mice. When they knocked down genes that regulated the formation of stress granules, they saw a 50% reduction in pancreatic cancer growth in mice.

“Now,” says Dr. Grabocka, “We needed tools to answer the question about obesity.” Obesity affects two-thirds of all adults in the US and 50% worldwide. It also doubles the risk and mortality for pancreatic cancer and increases the risk of other cancers. About 33% of pancreatic cancers are related to obesity, a number that is only expected to increase in the coming decades.

Researchers took two different types of mouse models of obesity — one genetically predisposed to overeating and one fed a high-fat diet — and looked at pancreatic cancer in these mice. Both models had five to eight times the amount of stress granules in their cancers than non-obese mice. “This suggested to us that the cancers in obese mice may depend on stress grains for growth. If we take away what cancer depends on for life, we kill the cancer.”

“When we blocked the formation of stress granules in these obese mice with pancreatic cancer, the results were quite surprising,” says Dr. Grabocka. “We saw either no cancer growth, or 1/14 and 1/20 the amount of growth we would see in obese mice with intact stress granules in the tumors.”

And the most noticeable difference was their overall survival. Normally, mice in these models of pancreatic cancer die very quickly, within 50-60 days. In obese mice whose tumor stress granules were blocked, 40% were cancer-free after 300 days, with no sign of cancer anywhere in the animals’ bodies. “This magnitude of response is extremely rare,” says Dr. Grabocka.

These experiments showed that stress granules were not only present in cancer cells, but that they actually drove cancer growth from the very beginning. “This is the first direct evidence linking stress granules to cancer progression,” says Dr. Grabocka.

Importantly, Dr. Grabocka also identified drug targets that could halt the formation of stress granules in obesity-related pancreatic cancer. The next steps are to test existing small molecule inhibitors to see if they can be translated for use in humans.

“Conditions of cellular stress, such as obesity, increase the number of stress granules present in cells and can trigger the formation of pancreatic and other cancers,” says Dr. Grabocka. “Because the effect we are seeing is so large, we think targeting the formation of stress granules could be a strong candidate for a new cancer therapy. Our work paves the way for a clinical trial in humans.”

This study was supported by an NIH/NCI R37CA160495 grant and a V Scholar Award and grants from the German Research Foundation. The Thomas Jefferson University Flow Cytometry Core, Translational Research/Pathology Core, and Animal Core are shared facilities supported in part by the National Cancer Center Support Grant (P30 CA056036) to Sidney Kimmel Cancer Center in Jefferson. The authors declare no conflicts of interest.

Article reference: Guillaume Fonteneau, Alexandra Redding, Hannah Hoag-Lee1, Edward S. Sim, Stefan Heinrich, Matthias M. Gaida, and Elda Grabocka, “Stress Beads Determine the Development of Obesity-Associated Pancreatic Cancer,” Cancer Discovery, DOI: 10.1158/2159- 8290.CD-21-1672, 2022.

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