胰腺导管腺癌（PDAC）作为最常见的胰腺癌类型，具有极高的恶性程度。在现阶段，PDAC的临床诊断和治疗乃是世界性的生物医学难题。机制上，除去KRAS的突变，胆固醇的高需求和Wnt/β-catenin信号的过度激活在PDAC的发展中也起到重要作用。申请人在分子水平上首次发现了胆固醇与Wnt蛋白受体Fzd5的特异性相互作用，并在PDAC细胞系和类器官模型中阐述了该相互作用对Wnt/β-catenin信号和PDAC发展的重要影响。基于以上发现，申请人拟在本项目中完整探索胆固醇与Fzd5相互作用的具体分子机制，在功能上拟通过细胞、类器官及小鼠模型全面地验证胆固醇通过Fzd5调控Wnt/β-catenin信号及PDAC生长的功能，将脂类代谢与肿瘤经典信号通路紧密联系起来，进一步推动PDAC的病理研究。最后，申请人拟设计Fzd5特异性小分子抑制剂并进行初步表征，为未来PDAC临床治疗提供新的思路。

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer with highly aggressive malignancy. The effective diagnosis and clinical therapy of PDAC are considered as world-wide challenges nowadays in the biomedical field. In addition to the oncogenic KRAS mutation, the heavy need of cholesterol and the over-activation of Wnt/β-catenin signaling also contribute majorly to the progression of PDAC mechanistically. We originally discovered that cholesterol molecule can interact specifically with the Wnt receptor Fzd5. Furthermore, we demonstrated that this interaction significantly affect Fzd5 and Wnt/β-catenin signaling and cell growth in the cell lines and organoids model of PDAC. Based on the findings above, we propose to deeply investigate the detail mechanism of cholesterol-Fzd5 interaction. And functionally, we propose to use cell, organoid and mouse model together to fully understand and validate the pivotal role of cholesterol in regulation Wnt/β-catenin signaling and PDAC progression. Taken together, we aim to robustly connect lipid metabolism with classical oncogenic cellular signaling in tumors in order to further fuel the pathological study of PDAC. Lastly, we plan to screen and design specific small molecules targeting Fzd5, which we believe would give rise to a new perspective in the future PDAC clinical therapy.