Researchers have uncovered that pancreatic cancer cells and nearby sensory nerves help each other grow stronger through a chemical signal called glutamate. Sensory nerves release glutamate, and pancreatic cancer cells have a receptor called GRIN2D that detects it. High levels of GRIN2D are linked to more advanced cancer. When cancer cells sense glutamate, they become more mobile, invade surrounding tissue, and grow faster. Blocking GRIN2D can stop this behavior.
Inside the cancer cell, glutamate triggers a chain reaction. It causes calcium to enter the cell, which activates proteins that increase EZH2, a molecule that turns off tumor-suppressing genes. This process also activates E2F1, which then boosts GRIN2D levels even more. This creates a self-reinforcing loop that keeps the cancer aggressive.
The signaling also works in the opposite direction. Cancer cells release a growth factor called TGFA that attracts more sensory nerves toward the tumor. These new nerves grow into the cancer and release even more glutamate, which further accelerates tumor growth and nerve invasion. This feedback loop explains why pancreatic cancer often spreads along nerves and causes severe pain.
In animal studies, removing GRIN2D greatly reduced tumor size, nerve growth inside tumors, and cancer-related pain, while also extending survival. Researchers also found direct physical contact points between nerves and cancer cells, similar to synapses, where neurotransmitters are delivered straight into tumor cells.
Overall, the findings reveal that pancreatic cancer hijacks nerve signaling to fuel its growth and pain, and targeting this nerve-cancer communication could open new treatment options.