Stress granule overload promotes obesity-related pancreatic cancer growth

Obesity is a known risk factor for at least 13 types of cancer, in part because it creates a persistent inflammatory condition. For years, a researcher has wondered if there’s more to the story than inflammation. New research from Dr. Elda Grabuka’s lab shows a new way obesity can lead to cancer formation in pancreatic cancer, which has 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 more abundant in obesity-related pancreatic cancer than in non-obese patients, and importantly, preventing their formation halted cancer growth in the animals. Research reveals a new direction for the development of cancer treatment.

Stress granules research is exploding right now, but there’s still a lot we don’t know regarding what they’re made of and how they work. This work is the first to show that stress granule overload enables tumor growth in the pancreas. Our experiments in mice also showed a complete reversal of cancer growth in the lab.”

Dr. Elda Grabuka, Investigator, Sidney Kimmel Cancer Center-Jefferson Health and Assistant Professor, Thomas Jefferson University

Stress granules are an unusual type of cell space. The cell generates these non-membranous organelles in response to stress, and to protect the cell from stress-induced self-destruction. It is a cellular reaction and defense mechanism found throughout animal and plant kingdoms. Even tomato plants produce stress granules to protect their cells. Researchers still do not know what these organelles consist of, and exactly how they protect the cell. However, it is clear that crabs have chosen this defense mechanism in their favour. Many cancers produce much higher levels of stress granules than normal cells, to help protect cancer cells from unleashing a natural self-destruct sequence.

Knowing this, Dr. Grabuka’s team created a mouse cancer model that inhibits the formation of stress granules in pancreatic cancer in mice. When they turned off genes that regulate stress granule formation, they observed a 50% reduction in pancreatic cancer growth in mice.

“Now, we had to use the tools to answer the question about obesity,” says Dr. Grabuca. Obesity affects two-thirds of all adults in the United States and 50% globally. It also doubles the risk of pancreatic cancer and death and increases the risk of other cancers. About 33% of pancreatic cancers are related to obesity, a number that is expected to increase in the coming decades.

The researchers took two different types of mouse models of obesity — one genetically predisposed to overeating, and one that was fed a high-fat diet — and looked at pancreatic cancer in these mice. Both models contained five to eight times the amount of stress granules in their cancers than non-obese mice. “This suggests to us that cancers in obese mice may depend on stress granules for their growth. When we remove the thing that cancer depends on for life, we are killing the cancer.”

“When we prevented the formation of stress granules in these obese mice with pancreatic cancer, the results were really surprising,” says Dr. Grabuca. “Either we saw no cancer growth, or 1/14 and 1/20 of the amount of growth we see in obese mice with healthy stress granules in tumors.”

The most striking difference was their overall survival. Usually in these models of pancreatic cancer, mice 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 volume of response is extremely rare,” says Dr. Grabuka.

These experiments showed that stress granules were not only present in the cancer cells, but were in fact driving the growth of the cancer initially. “This is the first direct evidence linking stress granules to the development of cancer,” says Dr. Grabuka.

Importantly, Dr. Grabuka’s lab has also identified drug targets that can stop stress granulosa formation 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.

“Cellular stress situations, such as obesity, increase the number of stress granules present in cells, and may lead to the formation of pancreatic and other cancers,” says Dr. Grabuca. “Because the effect we’re seeing is so large, we believe targeting stress granule formation 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 a NIH/NCI grant R37CA160495, a V Scholar Award, and grants from the German Research Foundation. The Thomas Jefferson University Flow Cytometry Center, Translational Research/Essence of Pathology, and Animal Basic are joint facilities supported in part by a National Cancer Center support grant (P30 CA056036) to the Sidney Kimmel Cancer Center at Jefferson. The authors report no conflict of interest.

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Journal reference:

Fontino, c. et al. (2022) Stress granules determine obesity-related pancreatic cancer development. Cancer discovery. doi.org/10.1158/2159-8290.CD-21-1672.