Pancreatic cancer remains one of the toughest malignancies to catch early, and it often resists conventional therapies. Researchers are therefore hunting for novel ways to halt the disease before it spreads. While it’s known that nerves can escort cancer cells, the role of the nervous system in the very first steps of pancreatic tumorigenesis has been unclear—until now.
“Perineural invasion is a well‑documented phenomenon where cancer cells travel along nerves to metastasize,” explains Jeremy Nigri, a postdoctoral fellow in David Tuveson’s laboratory at Cold Spring Harbor. “Our latest work shows that nerves are already active participants long before a visible tumor appears.”
Nerves Appear Prior to Tumor Formation
Using high‑resolution three‑dimensional imaging, Nigri’s team observed that a subset of fibroblasts called myCAFs release chemical cues that lure nearby nerve fibers. Once recruited, these nerves and myCAFs mingle within early pancreatic lesions, establishing a microenvironment that favors cancerous growth. The findings were recently reported in Cancer Discovery.
3D Imaging Uncovers Dense Neural Networks
The researchers applied whole‑mount immunofluorescence to capture volumetric images of lesions and surrounding cells. In two‑dimensional snapshots, nerves look like scattered specks; the 3D reconstructions, however, reveal an extensive, intertwined web of fibers wrapping around myCAFs throughout the lesions.
“Seeing the lesion in three dimensions was a revelation,” Nigri recalls. “It completely changed my perception of how early‑stage disease is organized.”
A Self‑Reinforcing Loop That Powers Cancer
Experiments in mouse models and human cell cultures identified a vicious cycle: myCAFs secrete signals that attract sympathetic nerve fibers, which in turn release norepinephrine. This neurotransmitter binds to receptors on fibroblasts, triggering a calcium surge that further activates myCAFs and stimulates pre‑cancerous growth. The heightened activity then draws even more nerves, perpetuating the loop.
Disrupting Nerve Signals Slows Tumor Progression
When the team chemically disabled the sympathetic nervous system with a neurotoxin, they observed a marked reduction in fibroblast activation and almost a 50 % drop in tumor size, underscoring the therapeutic potential of targeting this pathway.
Implications for Future Treatments
Because the nerve‑fibroblast interaction occurs so early, drugs that interrupt this communication could become valuable adjuncts to standard chemotherapy or immunotherapy. Existing medications such as doxazosin are already being considered for repurposing in this context.
“Our next goal is to pinpoint ways to block the crosstalk between myCAFs and nerves,” says Nigri. “With support from organizations like the Lustgarten Foundation and the Pancreatic Cancer Action Network, we hope to translate these insights into better outcomes for patients.”