“One phenomenon that is known is called perineural invasion,” says Jeremy Nigri, a postdoc in Professor David Tuveson’s lab at Cold Spring Harbor Laboratory (CSHL). “This means cancer cells will migrate within the nerve and use the nerve as a way to metastasize.”

Nerves Involved Before Tumors Form

Nigri and his colleagues at CSHL have now found evidence that the nervous system is involved much earlier than expected. Their research shows that nerves actively contribute to pancreatic cancer development even before full tumors appear.

Using advanced 3D imaging, the team observed that tumor promoting fibroblasts known as myCAFs release chemical signals that attract nearby nerve fibers. Once present, the myCAFs and nerve cells interact inside pancreatic lesions, helping create conditions that support cancer growth. The results were published in Cancer Discovery, a journal of the American Association for Cancer Research.

3D Imaging Reveals Dense Nerve Networks

To visualize these interactions, the researchers used a method called whole-mount immunofluorescence, allowing them to capture detailed three dimensional images of lesions and surrounding cells. In traditional 2D images, nerve fibers appear as small scattered dots. The 3D images told a very different story, revealing a thick and interconnected network of nerves woven throughout the lesions and wrapped around the myCAFs.

“When we first saw this picture, I was shocked,” Nigri says. “I couldn’t even imagine the lesion like this. I’d only ever seen it in 2D.”

A Feedback Loop That Fuels Cancer Growth

Experiments in mice and human cells uncovered what the researchers describe as a harmful cycle between myCAFs and nerves. The myCAFs release signals that draw in nerve fibers from the sympathetic nervous system, which controls the body’s fight or flight response.

Those nerve fibers release norepinephrine, a neurotransmitter that binds to the fibroblasts and causes a spike in calcium levels inside the cells. This calcium surge further activates the myCAFs, encouraging pre cancerous growth. At the same time, it attracts even more nerve fibers, strengthening a self sustaining loop that promotes tumor development.

Blocking Nerve Signals Slows Tumor Growth

The researchers also tested what would happen if this nerve activity were interrupted. “In one experiment, we use a neurotoxin to disable the sympathetic nervous system,” Nigri says. “We show reduced fibroblast activation and a nearly 50% reduction in tumor growth.”

Potential New Treatment Strategies

Because this interaction between myCAFs and nerves takes place so early, targeting it may offer a new therapeutic strategy. The findings suggest that existing medications, including doxazosin, could be useful when combined with established treatments such as chemotherapy or immunotherapy.

“The next step will be to study this more in detail and try to find a way to block the crosstalk between fibroblasts and nerves,” Nigri says. “With support from groups like the Lustgarten Foundation and Pancreatic Cancer Action Network, we hope to one day help improve patient outcomes.”