Researchers Identify Hormone Behind Obesity-Induced Pancreatic Cancer

Obesity increases the body's need for insulin, forcing cells in the pancreas known as beta cells to ramp up insulin production to maintain blood sugar levels.

Scientists have thought that this excessive insulin secretion is one of the factors that drives the development of obesity-induced pancreatic cancer. But a new study published in Nature Communications challenges this idea.

The culprit, according to Yale School of Medicine (YSM) scientists, is not insulin, but another hormone called cholecystokinin.

“We discovered that the pancreas inappropriately produces the hormone cholecystokinin in response to obesity and that this hormone was a key driver of obesity-associated pancreatic cancer in mice,” says Mandar Deepak Muzumdar, MD, co-senior author of the study and associate professor of genetics and of internal medicine at YSM.

In an earlier study, Muzumdar and his team found that obesity causes beta cells to produce cholecystokinin in mice. In addition, mice predisposed to develop pancreatic ductal adenocarcinoma (PDAC)—the most common and aggressive form of pancreatic cancer—have significantly worse tumor progression when there are higher levels of cholecystokinin in the pancreas.

Interestingly, beta cells that release cholecystokinin tend not to produce much insulin. So, how does obesity push beta cells to make cholecystokinin instead?

To answer that question, the researchers turned to the Cflows computational pipeline developed by the Krishnaswamy lab, which yields insights into the dynamic states of a single cell that influence its metabolism or immune response.

“All beta cells lie on a continuum,” says Smita Krishnaswamy, PhD, co-senior author and associate professor of genetics at YSM and of computer science at Yale Engineering.

Recent studies have shown that beta cells are much more diverse than previously thought and that this diversity can be changed by factors such as obesity or diabetes. The investigators found that obesity induced the production of cholecystokinin in a subset of beta cells. By using the Krishnaswamy Lab’s TrajectoryNet method—a machine learning tool for tracing cellular changes over time—the researchers tracked the trajectory of the cholecystokinin-producing cells and correlated it to the activities of its genes and signaling molecules.

“This analysis can be used to find the origin of a particularly pernicious cell type and help figure out the mechanisms that caused it to become pernicious,” says Krishnaswamy, who is a member of Yale Cancer Center and the Wu Tsai Institute.

The researchers found that cholecystokinin-producing beta cells in obese mice were derived from supposedly healthy, insulin-producing beta cells. Further, by tracking cellular changes as obesity progressed, they observed a strong correlation between cholecystokinin production and the presence of stress markers within the cell. This suggests that cholecystokinin production may be a protective response against cellular stress caused by obesity.

“It's only under this context of stress where these beta cells adapt towards a cholecystokinin expression state,” says Muzumdar, who is a member of the Yale Cancer Biology Institute.

The pancreas, which sits behind the stomach, has two portions. The endocrine portion includes beta cells and others involved in hormone secretion. The exocrine portion, which makes up the majority of the pancreas and is involved in digestion, is the source of PDAC.

The researchers found that as beta cells began to change, cells in the exocrine portion of the pancreas also transformed. When that happened, exocrine cells became highly susceptible to tumor development.

“Historically, those two compartments have been studied by separate investigators: endocrinologists on the endocrine side and gastroenterologists on the exocrine side. And it’s been thought that they are distinct compartments with functional roles that don’t interact,” Muzumdar adds.

These findings show they do interact, an important revelation as people with endocrine diseases such as diabetes often have a higher risk of developing exocrine diseases like pancreatic cancer and pancreatitis.

To observe cholecystokinin’s effects more directly, the researchers altered its levels in lean and obese mice. They found that large quantities of cholecystokinin produced by beta cells in lean mice were enough to promote PDAC development. On the other hand, removing the production of cholecystokinin in obese mice through gene knockout greatly reduced tumor growth.

“That showed that the cholecystokinin hormone was necessary and sufficient to promote the development of obesity-driven pancreatic cancer,” Muzumdar says.

This finding may open a new avenue for diagnosing PDAC by way of cholecystokinin. “It turns out that cholecystokinin is secreted into the bloodstream, so it may be measurable using biochemical tests,” Muzumdar says. An increased level of the hormone in the blood could potentially serve as a risk marker for developing PDAC.

The results of the study also highlight a close interaction between the endocrine and exocrine portions of the pancreas that is often overlooked.

“The mechanisms involved in the exocrine-endocrine interactions have not been well described until now,” Muzumdar says. “Our study is one of the key examples that shows that signals sent between the two play a very important role in cancer. Therefore, targeting these signals may unlock a new approach for pancreatic cancer prevention.”