胰腺癌发病早期易发生神经浸润（PNI）转移，预后极差，而PNI发生机制仍未明确。我们前期研究发现肿瘤相关巨噬细胞（TAMs）可致胰腺癌细胞分泌高水平基质金属蛋白酶1（MMP-1），并促进其沿神经转移。据报道小鼠背根神经节表达MMP-1受体PAR-1，胰腺癌细胞表达神经肽P物质（SP）受体NK-1R，提示胰腺癌细胞与背根神经节间可能存在MMP-1/PAR-1环路，诱导癌细胞沿神经转移。为明确TAMs上调胰腺癌细胞MMP-1促进其神经转移机制，本项目拟开展①验证MMP-1/PAR-1/SP/NK-1R环路；②构建壳聚糖神经导管环套鼠坐骨神经，填充胰腺癌细胞和TAMs模拟肿瘤微环境，MRI动态示踪PNI，体内模型验证MMP-1促进胰腺癌PNI；③利用课题组已制备免疫纳米载体荷瘤鼠体内靶向输送siRNA，沉默MMP-1基因，验证MMP-1/PAR-1作为新靶点以抑制PNI，为胰腺癌诊治提供新思路。

Perineural invasion (PNI) in pancreatic cancer is a common pathologic phenomenon even in the early stages and PNI is correlates with poor prognosis of pancreatic cancer patients. However, the mechanism of PNI is unclear yet. Our previous studies shown that the tumor associated macrophages (TAMs) up-regulated MMP-1 levels apparently in pancreatic cancer cells, and enhanced the perineural invasion. Previous studies shown that protease-activated receptor 1 (PAR-1) is expressed in mouse dorsal root ganglia (DRG), which could be activated by MMP-1. And pancreatic cancer cells expressed the receptor of neurotransmitter substance P (SP), NK-1R. The above evidence indicated that there would be a cytokine loop mediated by MMP-1/PAR-1 between pancreatic cells and DRG, which induced the occurrence of PNI. In order to explore the molecular mechanisms underlying that TAMs promoted PNI of pancreatic cells via up-regulating MMP-1, in this project we intends to carry out the following researches: ① Experiments to verify the MMP-1/PAR-1/SP/NK-1R loop between pancreatic cancer cells and DRG. ② Chitosan nerve conduits containing nerves, cancer cells and TAMs would be used to mimic tumor microenvironment, and MR imaging would be used to tracer early PNI in rats. ③ To verify the potential therapeutic target inhibiting pancreatic cancer PNI, a nano vector would be used to deliver siRNA silencing MMP-1 targeted pancreatic cancer cells in mice. Our studies would provide a new idea for pancreatic cancer treatments.