Study finds stress-related nerves may fuel pancreatic cancer growth

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Oregon Health & Science University researchers have found that certain nerves that play an integral role in the body’s “fight or flight” stress response can support pancreatic tumor growth. These nerves, called sympathetic nerves, grow directly into pancreatic tumors and communicate with cancer cells and nearby support cells known as cancer-associated fibroblasts. This communication can change the tumor’s behavior in ways that help pancreatic cancer grow.

“We were interested in gaining new insights into how sympathetic nerves interact with all of the other cells within that pancreatic cancer ecosystem, and how these interactions influence pancreatic cancer,” said the study’s first author, Ariana Sattler, Ph.D., who completed the work as a doctoral candidate in the OHSU Graduate Program in Biomedical Sciences. The findings are published in JCI Insight.

Scientists have long studied components of the tumor ecosystem such as the fibroblasts, immune and blood vessel cells but often overlooked nerves, she said. One central reason is that the main bodies of nerve cells sit outside tumors, making them harder to detect with traditional sequencing tools.

To study the role of nerves in cancer, the team drew from prior cancer and neuroscience research to develop new marker panels and create a model to selectively remove sympathetic nerves from the mouse pancreas.

Their study results showed that sympathetic-associated genes are associated with poor survival in patients with pancreatic cancer, and removal of pancreatic nerves resulted in smaller tumors—but only in female mice. That result suggests that sympathetic nerves are an important player in pancreatic cancer, and that sex hormones may contribute to how nerves and tumors communicate.

“The sex-specific tumor phenotype that we observed was very unexpected,” said Ece Eksi, Ph.D., assistant professor in the OHSU Knight Cancer Institute’s Cancer Early Detection Advanced Research Center and the study’s senior author.

Eksi’s lab is now continuing several projects to explore further differences in the tumor microenvironment in the absence of sympathetic nerves and how sex hormones may influence this nerve-cancer connection.

Eksi said the nervous system acts as a kind of body-wide monitoring and feedback network, constantly sensing what is happening in all organs. Because the pancreas is a gland that regularly responds to nerve signals and hormones, it may be especially sensitive to sympathetic inputs in the context of cancer.

The findings are still early, but the researchers say the work could be built upon to someday inform new treatments. Some scientists in the cancer-neuroscience space are already testing whether preexisting drugs for other uses, such as beta blockers which are typically used to manage cardiovascular conditions and dampen stress signals, might help hamper certain cancers. The recent emergence of devices that stimulate major nerves, currently used for other diseases, could one day be explored in cancer.

For now, Sattler said the study highlights a growing field known as cancer neuroscience—and a simple idea: tumors do not grow alone. They interact and are supported by several body systems surrounding them, including the nervous system. Understanding those connections could open new paths to understanding this fatal disease that needs more treatment and prevention options.

The nervous system plays an active role in pancreatic cancer development, researchers discover