胰腺癌是恶性程度最高的肿瘤之一，常早期发生转移。胰腺癌相关成纤维细胞 (CAF）的活化是胰腺癌侵袭转移的重要因素。TGF-β信号通路是调控CAF活化的关键通路。项目组前期研究发现LRG-1是调控胰腺癌侵袭转移的重要因子，且LRG-1已被证实可通过endoglin激活TGF-β下游Smad-1/5/8信号通路。本项目组预实验亦发现LRG-1表达与胰腺癌肝转移相关，且外源性LRG-1能够调控胰腺癌相关CAF的活化。基于以上证据，本项目组提出如下假说：LRG-1可通过结合endoglin激活TGF-β信号通路，活化CAF，从而促胰腺癌转移。本项目拟先研究LRG-1与胰腺癌转移及CAF活化的关系，进而探讨endoglin/TGF-β信号通路介导了LRG-1调控CAF活化的作用；最后通过在体干预实验，明确LRG-1中和抗体对转移性胰腺癌的治疗作用。通过本研究，为治疗转移性胰腺癌寻找新的靶点。

Pancreatic ductal adenocarcinoma (PDAC) is the one of most malignant tumors and always associate with early metastasis. PDAC associated fibroblast (CAF) is the key factor which promotes the metastasis of PDAC. TGF-β signaling pathway is the key regulator of activating CAF and modulating the phenotype of CAF. Our team has previous found that leucine-rich-alpha-2-glycoprotein 1 (LRG-1) is essential for promoting the PDAC metastasis. And LRG-1 facilitate the malignant behavior of malignant tumors through binding endoglin and activating TGF-β download signaling pathways (Smad-1/5/8). Our previous researches find out that LRG-1 expressions are correlated with PDAC liver metastasis, and LRG-1 could further activate human primary CAF. Based on above evidence, we hypothesis that LRG-1 actives TGF-β signaling pathway via the interaction with endoglin, thus to modulate the activation of CAF and to promote PDAC metastasis. We firstly would like to investigate the relationship between LRG-1 expression and PDAC metastasis, and the relationship between LRG-1 expression and the activation of CAF. Next, to explore the effect of LRG-1 on the CAF in PDAC cells. Moreover, to demonstrate the exact mechanism of how LRG-1 activates CAF in PDAC cells. Fellow animal models are used to prove the mechanism of how LRG-1 promotes PDAC metastasis. This project is aimed to identify the exact role of LRG-1 modulated PDAC metastasis, and further to clarify LRG-1 is the therapeutic target for treating metastatic PDAC. From this, we could search the new target to treat PDAC metastasis.