Wnt信号通路介导胰腺星形细胞旁分泌FGF9调控FST影响胰腺癌细胞侵袭迁移能力的分子机制研究

胰腺星形细胞（PSC）是胰腺癌肿瘤微环境的关键性成分，针对PSC的靶向治疗策略极具临床应用前景。申请人长期聚焦于PSC与胰腺癌细胞间相互作用的研究。前期预实验显示，在活化PSC中，FGF9表达上调最为明显，且受到Wnt信号通路调控。功能实验提示,PSC旁分泌的FGF9通过调控胰腺癌细胞中的卵泡抑素（FST）表达促进其侵袭迁移。进一步研究表明，胰腺癌细胞膜上的FGFR发生表达上调和亚型转变。我们还筛查分析了FGFR结合蛋白，并用多种方法预测调控FST的关键转录因子。我们推测：Wnt/FGF9/FST信号轴介导了PSC对胰腺癌细胞的作用。本项目拟在预实验基础上结合体内外模型及人胰腺癌样本，探讨（1）PSC中FGF9的表达及其调控机制；（2）FGF9/FST通路对胰腺癌细胞EMT及侵袭迁移能力的影响；(3）FGF9调控胰腺癌细胞中FST表达的分子机制。期望从PSC角度为胰腺癌诊疗提供新思路。

Pancreatic stellate cells (PSCs) are key components of tumor microenvironment in pancreatic cancer with great promise for targeted therapy. Our preliminary experiments showed that FGF9 expression is upregulated in human activated PSCs through Wnt signaling pathway. Functional experiments suggested that FGF9 upregulated follistatin (FST) expression and promoted the invasion and migration of pancreatic cancer cells (PCCs). We also found that FGFR was upregulated with receptor subtype conversion in PCCs. Additionally, we screened and analyzed FGFR binding proteins and used multiple methods to predict the key transcription factors that regulate FST. We speculate that the Wnt/FGF9/FST signal axis mediates the effects of PSCs on PCCs. Based on our preliminary experiment, this research intends to explore (1) FGF9 expression and its regulation in PSCs; (2) the effects of FGF9/FST pathway on the epithelial-mesenchymal transition (EMT), invasion and migration of PCCs; (3) the molecular mechanism underlying FST expression regulation by FGF9 in PCCs. Our study helps to clarify the complex interaction between PSCs and PCCs, and shed light on pancreatic cancer treatment targeting PSCs.