Structural and molecular insight into antibody recognition of dynamic neoepitopes in membrane tethered MUC1 of pancreatic cancer cells and secreted exosomes.
Hajime WakuiYasuhiro YokoiChieko HoridomeToyoyuki OseMin YaoYoshikazu TanakaHiroshi HinouShin-Ichiro NishimuraPublished in: RSC chemical biology (2023)
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 O -glycans found in normal cells. Comprehensive assessment of the essential epitope for SN-131 indicates that PANC-1 cells produce dominantly MUC1 with aberrant O -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 ( K D = 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 O -glycosylated "dynamic neoepitopes" found in the membrane-tethered MUC1 is a promising therapeutic strategy for improving the treatment outcome of patients with pancreatic cancer.
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