GPR81/Fyn信号轴促进胰腺癌发生发展的作用机理及小分子干预研究

代谢物异常在细胞恶性转化过程中具有重要作用，G蛋白偶联受体（GPCR）能感应多种代谢物的变化，提示以代谢物为配体的GPCR可能参与了肿瘤的病理过程。在前期研究中，我们发现乳酸受体GPR81在胰腺癌中高表达且与病人的预后密切相关。CRISPR-Cas9介导的GPR81基因敲除可显著抑制胰腺癌细胞的生长和转移。初步机理研究表明，乳酸可诱导GPR81直接结合并活化Src激酶家族成员Fyn。通过构建高效的筛选体系，我们发现了全新的GPR81小分子拮抗剂IBS-118。基于以上工作基础，本项目将利用胰腺癌细胞模型、荷瘤模型及转基因小鼠模型，阐明GPR81调控Fyn激酶活化的分子机制，揭示GPR81/Fyn信号轴在胰腺癌发生发展中的作用，并详细评价IBS-118的体内外抗胰腺癌活性。本项目的实施能揭示乳酸受体GPR81在胰腺癌中的作用，阐明新的信号转导通路，以期为胰腺癌治疗提供潜在分子靶标。

Metabolite abnormalities are closely related to malignant transformation. G protein-coupled receptors (GPCRs) can recognize a variety of metabolites, indicating that metabolite-sensing GPCRs may also be involved in the pathological process of cancer. In the previous study, we found that the lactate receptor GPR81 is highly expressed in pancreatic cancer and is associated with patient survival. CRISPR-Cas9-mediated gene knockout of GPR81 can significantly inhibit the growth, invasion and metastasis of pancreatic cancer. Preliminary mechanism studies indicate that GPR81 directly bind to and activate Fyn kinase following lactate treatment. We have discovered a novel GPR81 antagonist IBS118 using Tango and Glosensor assay. Based on our previous work, we intend to use the pancreatic cancer cell model, tumor-bearing model and transgenic mouse model to elucidate the mechanism of GPR81 regulating Fyn-related signaling pathway in pancreatic cancer, reveal the role of GPR81/Fyn signaling axis in pancreatic cancer growth and metastasis, and evaluate the anti-pancreatic cancer activity of IBS118. This project will reveal the role of GPR81 in the development of pancreatic cancer, providing potential targets for the treatment of pancreatic cancer.