Nerves Actively Fuel Early Pancreatic Cancer Development, Studies Reveal
New research shows the nervous system contributes to pancreatic cancer development before tumors fully form, with nerve fibers and support cells creating a self-sustaining loop that promotes cancer growth. Blocking nerve activity reduced tumor growth by nearly 50% in experiments.
Researchers have found evidence that the nervous system is involved in pancreatic cancer development much earlier than expected, actively contributing to the disease even before full tumors appear. The findings, published in Cancer Discovery, a journal of the American Association for Cancer Research, suggest a new treatment strategy for one of the most difficult cancers to diagnose and treat.
Using advanced 3D imaging, the team at Cold Spring Harbor Laboratory 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.
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 revealed a thick and interconnected network of nerves woven throughout the lesions and wrapped around the myCAFs.
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.
The researchers also tested what would happen if this nerve activity were interrupted. In one experiment, using a neurotoxin to disable the sympathetic nervous system showed reduced fibroblast activation and a nearly 50% reduction in tumor growth.
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.
Researchers already understand that nerves can help cancer spread through a phenomenon called perineural invasion, which means cancer cells will migrate within the nerve and use the nerve as a way to metastasize. The new research shows the nervous system's involvement begins much earlier in the disease process.
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. With support from groups like the Lustgarten Foundation and Pancreatic Cancer Action Network, researchers hope to one day help improve patient outcomes.