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

胰腺导管腺癌（PDAC）的神经浸润与高局部复发率和严重神经病理性疼痛综合征相关。我们最近的研究结果指出，胰腺中外周神经的雪旺细胞在癌症来源的IL-6和CXCL 12信号转导中被激活，并迁移到前体PanIN病变以启动神经侵袭。在本项目中，我们将进行第一次真正的机制研究的作用，外周胶质细胞/雪旺细胞在PDAC的进展。为此，我们将杂交基因工程小鼠模型（GEMM）PDAC与转基因GFAP-胸苷激酶系，允许选择性耗尽激活的神经胶质细胞后更昔洛韦管理。将分析生成的PDAC小鼠（KC;GFAP-tk和KPC;GFAP-tk）的PanIN进展至癌症、化学反应性和存活率。下一步，我们将分析神经侵袭的程度，神经密度和大小，以及有或没有胶质细胞耗竭的小鼠的疼痛感觉。在最后一步中，将在胰腺内胶质细胞耗尽后比较第一和第二级伤害感受神经元的激活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.