Wakui Hajime, Yokoi Yasuhiro, Horidome Chieko, Ose Toyoyuki, Yao Min, Tanaka Yoshikazu, Hinou Hiroshi, Nishimura Shin-Ichiro
Field of Drug Discovery Research, Faculty of Advanced Life Science, and Graduate School of Life Science, Hokkaido University N21 W11 Kita-ku Sapporo 001-0021 Japan
Field of X-ray Structural Biology, Faculty of Advanced Life Science, and Graduate School of Life Science, Hokkaido University N10 W8 Kita-ku Sapporo 060-0810 Japan.
RSC Chem Biol. 2023 May 24;4(8):564-572. doi: 10.1039/d3cb00036b. eCollection 2023 Aug 3.
Pancreatic cancer is highly metastatic and has poor prognosis, mainly due to delayed detection, often after metastasis has occurred. A novel method to enable early detection and disease intervention is strongly needed. Here we unveil for the first time that pancreatic cancer cells (PANC-1) and secreted exosomes express MUC1 bearing cancer-relevant dynamic epitopes recognized specifically by an anti-MUC1 antibody (SN-131), which binds specifically core 1 but not core 2 type -glycans found in normal cells. Comprehensive assessment of the essential epitope for SN-131 indicates that PANC-1 cells produce dominantly MUC1 with aberrant -glycoforms such as Tn, T, and sialyl T (ST) antigens. Importantly, SN-131 showed the highest affinity with MUC1 bearing ST antigen at the immunodominant DTR motif ( = 1.58 nM) independent of the glycosylation states of other Ser/Thr residues in the MUC1 tandem repeats. The X-ray structure revealed that SN-131 interacts directly with Neu5Ac and root GalNAc of the ST antigen in addition to the proximal peptide region. Our results demonstrate that targeting -glycosylated "dynamic neoepitopes" found in the membrane-tethered MUC1 is a promising therapeutic strategy for improving the treatment outcome of patients with pancreatic cancer.
胰腺癌具有高度转移性且预后较差，主要原因是检测延迟，通常在转移发生后才被发现。因此，迫切需要一种能够实现早期检测和疾病干预的新方法。在此，我们首次揭示胰腺癌细胞（PANC-1）及其分泌的外泌体表达的MUC1带有癌症相关的动态表位，可被抗MUC1抗体（SN-131）特异性识别，该抗体特异性结合正常细胞中不存在的核心1型而非核心2型聚糖。对SN-131关键表位的综合评估表明，PANC-1细胞主要产生具有异常糖型的MUC1，如Tn、T和唾液酸化T（ST）抗原。重要的是，SN-131在免疫显性DTR基序处与带有ST抗原的MUC1表现出最高亲和力（Kd = 1.58 nM），且与MUC1串联重复序列中其他Ser/Thr残基的糖基化状态无关。X射线结构显示，SN-131除了与近端肽区域相互作用外，还直接与ST抗原的Neu5Ac和根部GalNAc相互作用。我们的结果表明，靶向膜结合型MUC1中发现的O-糖基化“动态新表位”是改善胰腺癌患者治疗效果的一种有前景的治疗策略。
