The impact of intrapancreatic glia cell depletion on tumor progression and pain in pancreatic cancer

• Applicant: Professor Dr. Ihsan Ekin Demir
• Subject Area: General and Visceral Surgery ; Gastroenterology
• Term: from 2020 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 445708649

Neural invasion is associated with the high local recurrence rate and the severe neuropathic pain syndrome in ductal adenocarcinoma of the pancreas (PDAC). Our recent findings point out that Schwann cells of peripheral nerves in the pancreas become activated over cancer-derived IL-6 and CXCL12-signaling and migrate to the precursor PanIN lesions to initiate neural invasion. In the present project, we shall perform the first truly mechanistic study on the role of peripheral glia/Schwann cells in the progression of PDAC. For this purpose, we shall interbreed genetically engineered mouse models (GEMM) of PDAC with the transgenic GFAP-thymidine-kinase line that allows selective depletion of activated glia upon ganciclovir administration. The generated PDAC mice (KC;GFAP-tk and KPC;GFAP-tk) will be analyzed for PanIN progression to cancer, for chemoresponsiveness, and survival rate. In the next step, we are going to analyze the extent of neural invasion, nerve density and size, and pain sensation in mice with or without glia depletion. In the final step, the activation of first and second order nociceptive neurons, as well as the activity of spinal microglia shall be compared after depletion of intrapancreatic glia. The results of the planned project bear the potential of uncovering Schwann cells as a novel therapeutic target in PDAC.

• DFG Programme: Research Grants