Pancreatic cancer has many nerves. Notoriously difficult to detect, the disease also often resists traditional treatment. Thus, researchers are urgently looking for new ways to disrupt tumor formation. Although scientists know that the nervous system can help cancer spread, its role in the early stages of the disease remains unclear. “One phenomenon that is known is called perineural invasion,” says Jeremy Nigri, a postdoctoral fellow in Professor David Tuveson’s lab at Cold Spring Harbor Laboratory (CSHL). “That means the cancer cells will migrate into the nerve and use the nerve as a way to metastasize.”
Now, Nigri and his colleagues at CSHL have discovered that the nervous system plays an active role in the development of pancreatic cancer, even before tumors form. Using 3D imaging, they discovered that tumor-promoting fibroblasts called myCAFs send signals to attract nerve fibers. MyCAFs and nerve cells then work together within the pancreatic lesions to create a favorable environment for cancer growth. The findings are reported in Discovery of Cancera journal of the American Association for Cancer Research.
A technique called whole-mount immunofluorescence allowed Tuveson’s team to take 3D pictures of the lesions and surrounding cells. Where standard 2D images show thin nerve fibers as scattered tiny dots, 3D images reveal a dense network of nerves running through and around myCAFs and lesions. “When we first saw this photo, I was shocked,” says Nigri. “I couldn’t even imagine the damage like that. I’d only ever seen it in 2D.”
Nigri and his colleagues conducted a series of experiments in mice and human cells that revealed a vicious cycle between myCAF and nerves. They found that myCAFs send out signals that attract nerve fibers from the sympathetic nervous system, which is responsible for our fight-or-flight response. These nerve fibers release the neurotransmitter norepinephrine, which binds to the fibroblasts and triggers a calcium spike that further activates the myCAFs. This spike not only promotes precancerous growth, but also pulls on even more nerve fibers, locking the system into a dangerous self-reinforcing loop.
In an experiment, we use a neurotoxin to disable the sympathetic nervous system. We show reduced fibroblast activation and almost a 50% reduction in tumor growth.”
Jeremy Nigri, postdoc, CSHL
Because the myCAF nerve loop occurs so early, interrupting this cycle could lead to potential new treatments. The findings suggest that clinically available drugs, including doxazosin, may be effective when combined with standard treatments such as chemotherapy or immunotherapy. “The next step will be to study it in more detail and try to find a way to block the junction between fibroblasts and nerves,” says Nigri. “With the support of groups like the Lustgarten Foundation and the Pancreatic Cancer Action Network, we hope to one day help improve patient outcomes.”
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