Chronic stress accelerates pancreatic cancer tumorigenesis via promoting the acinar induced increasing of Slc6a2 in nerve

Background: Chronic psychosomatic stress has been regarded as a critical risk factor for the development of pancreatic cancer, and the interaction between nerve and tumor seems contributed to this situation. In this study, we aim to find out the possible mechanisms on how tumor-nerve crosstalk promote the pancreatic tumorigenesis in stress condition. Methods: A transgenic mice harbored spontaneous pancreatic cancer and a restraint model were used in vivo, and the 3-dimensional acinar culture and PC12 cell were adopted as the in vitro model. High throughput mRNA sequencing was used to explore and the western blotting was adopted to verify the possible mechanisms involved in this process. Results: From the clinical data we reveled that pancreatic cancer patients harbored a higher level of psychosomatic stress. Similarly, iv vivo model showed chronic restraint stress facilitated the tumorigenesis of pancreatic cancer and stress hormone promoted the formation of acinar-to-ductal metaplasia (ADM) in vitro. Besides, we also found that nerve inhibition suppressed the chronic stress driven rapid developing of pancreatic cancer. Indeed, the results suggested that the nerve derived Slc6a2 may the key of chronic stress induced pancreatic initiation acceleration, and its upregulation in nerve was due to stress induced activating of Notch1-NGF axis in pancreatic precancerous cell. What’s more, we found duloxetine, a Slc6a2 blocker, could suppresses the tumorigenesis of pancreatic cancer in chronic stress. Conclusion: Chronic stress accelerates the development of pancreatic cancer via promoting the nerve derived Slc6a2 stimulated by the Notch1-NGF axis in pancreatic precancerous cell.