胰腺癌易发生神经转移而机制未明。我们在鼠坐骨神经胰腺癌浸润模型和背根神经节三维培养实验发现，神经纤维表面包绕的施旺细胞促进癌细胞神经转移；进一步预实验显示芯片筛选差异细胞因子中的TIMP1/CCL7是沟通胰腺癌细胞-施旺细胞关键因子、协同促进癌细胞迁移和侵袭。本课题拟进一步研究胰腺癌细胞通过TIMP1/PI3K/AKT激活施旺细胞促进神经重构以及施旺细胞通过CCL7/TIMP1/TWIST1促进胰腺癌向神经趋化的作用。建立转基因鼠模型验证胰腺细胞恶变进程TIMP1激活施旺细胞、推动神经侵犯作用；利用鼠坐骨神经胰腺癌浸润模型和课题组纳米技术验证上述旁分泌及示踪肿瘤神经转移，并联合负载shTIMP1和吉西他滨纳米微粒阻断旁分泌TIMP1及增敏吉西他滨、抑制肿瘤神经转移。最后，结合血清TIMP1、CCL7和临床各指标建立胰腺癌神经转移预测模型。本项目为胰腺癌神经转移诊断、治疗及预后提供新的思路。

The mechanism of neural metastasis in pancreatic cancer is unknown. We demonstrated that Schwann cells, wrapping on the surface of nerve fibers, significantly promoted pancreatic cancer cell metastasis to the nerve both in the mouse model of ischial nerve infiltration in vivo and in the three-dimensional culture model of dorsal root ganglion in vitro. We screened out TIMP1 and CCL7 by Cytokine Antibody Array Assay. In the following experiments we found that TIMP1 secreted by pancreatic cancer cells activated Schwann cells. Moreover, activated Schwann cells secreted CCL7 to promote the migration and invasion of cancer cells and up-regulate the expression of TIMP1 in pancreatic cancer cells. So we hypothesized that TIMP1/CCL7 are the key molecules to communicate with pancreatic cancer cells and Schwann cells. In order to elucidate the key pathways involved in neural metastasis of pancreatic cancer, we intend to investigate the specific mechanism that pancreatic cancer cells activate Schwann cells and promote nerve remodeling through TIMP1/PI3K/AKT, while Schwann cells promote nerve chemotactic of pancreatic cancer through CCL7/TIMP1/TWIST1. A transgenic mouse model will be established to verify that TIMP1 can activate Schwann cells and promote nerve invasion during the development of pancreatic cancer. The above paracrine loop and the tumor neural metastasis will be identified by the mouse model of ischial nerve infiltration and our established tracing nanotechnology. Then we plan to design immuno-nanoparticles loading shTIMP1 and gemcitabine to block the loop, increase the efficacy of gemcitabine and inhibit tumor nerve metastasis. Finally, based on the results of this study and some clinical indicators, we will establish a model for the prediction of pancreatic cancer neural metastasis. Overall, this study aims at providing new ideas and potential targets for the diagnosis, treatment and prognosis of pancreatic cancer neural metastasis.