胰管腺癌（PDAC）是一种高度致命的肿瘤，治疗选择有限。在这里，我们确定了趋突因子绑定蛋白（SDCBP），也称为syntenin1，作为促进PDAC肿瘤进展的新靶标因子。我们还探索了抑制SDCBP表达的治疗策略。我们在患有PDAC的患者样本、人体器官模型、LSL-KrasG12D/+小鼠、LSL-Trp53R172H/+和Pdx1-Cre（KPC）小鼠模型以及PDX小鼠模型中进行了研究。本研究进行了免疫染色、集落形成实验、乙炔基-2-脱氧尿嘧啶（EdU）检测、实时细胞分析、细胞凋亡实验、自动化细胞追踪、侵袭小突起检测和明胶降解实验、共免疫沉淀和拉萨实验。高-SDCBP组中的中位总生存率和无复发生存率显著短于低-SDCBP组。体内和体外研究表明，SDCBP促进PDAC增殖和转移。机械性地，SDCBP抑制CK1δ/ε介导的YAP-S384/S387磷酸化，进一步通过直接与YAP1相互作用抑制β-TrCP介导的YAP1泛素化和蛋白酶体降解。SDCBP主要通过其PDZ1结构域与YAP1的TAD区域相互作用。临床前KPC小鼠队列证明，硫代芬醇锌（ZnPT）通过抑制SDCBP抑制PDAC肿瘤进展。因此，ZnPT可能是抑制PDAC进展的有希望的治疗策略，可通过抑制SDCBP实现。©作者（或其雇主）2023年。无商业再利用。请参阅权利和权限。出版者：BMJ。

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal tumour with limited treatment options. Here, we identified syndecan binding protein (SDCBP), also known as syntenin1, as a novel targetable factor in promoting PDAC tumour progression. We also explored a therapeutic strategy for suppressing SDCBP expression.We used samples from patients with PDAC, human organoid models, LSL-KrasG12D/+mice, LSL-Trp53R172H/+ and Pdx1-Cre (KPC) mouse models, and PDX mouse models. Immunostaining, colony formation assay, ethynyl-2-deoxyuridine incorporation assay, real-time cell analysis, cell apoptosis assay, automated cell tracking, invadopodia detection and gelatin degradation assays, coimmunoprecipitation, and pull-down assays were performed in this study.The median overall survival and recurrence-free survival rates in the high-SDCBP group were significantly shorter than those in the low-SDCBP group. In vitro and in vivo studies have demonstrated that SDCBP promotes PDAC proliferation and metastasis. Mechanically, SDCBP inhibits CK1δ/ε-mediated YAP-S384/S387 phosphorylation, which further suppresses β-TrCP-mediated YAP1 ubiquitination and proteasome degradation by directly interacting with YAP1. SDCBP interacts with the TAD domain of YAP1, mainly through its PDZ1 domain. Preclinical KPC mouse cohorts demonstrated that zinc pyrithione (ZnPT) suppresses PDAC tumour progression by suppressing SDCBP.SDCBP promotes the proliferation and metastasis of PDAC by preventing YAP1 from β-TrCP-mediated proteasomal degradation. Therefore, ZnPT could be a promising therapeutic strategy to inhibit PDAC progression by suppressing SDCBP.© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.