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

胰腺导管腺癌（PDAC）的神经侵犯与高局部复发率和严重神经性疼痛综合征有关。我们最近的研究结果指出，胰腺周围神经的雪旺细胞被癌症来源的IL-6和cxcl12信号激活，并迁移到前体PanIN病变，启动神经侵袭。在本项目中，我们将首次对外周胶质细胞/雪旺细胞在PDAC进展中的作用进行真正的机制研究。为此，我们将PDAC的基因工程小鼠模型（GEMM）与转基因gfap -胸苷激酶系杂交，该基因工程小鼠模型允许在更昔洛韦给药后选择性地消耗活化的胶质细胞。生成的PDAC小鼠（KC；GFAP-tk和KPC；GFAP-tk）将被分析PanIN向癌症的进展、化学反应性和生存率。下一步，我们将分析神经侵犯的程度，神经密度和大小，以及有无神经胶质细胞缺失的小鼠的痛觉。最后一步，在胰腺内胶质细胞耗损后，比较一、二级伤害感觉神经元的激活情况，以及脊髓小胶质细胞的活性。计划项目的结果有可能揭示雪旺细胞作为PDAC的新治疗靶点。

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.