Issue 8, 2023

Structural and molecular insight into antibody recognition of dynamic neoepitopes in membrane tethered MUC1 of pancreatic cancer cells and secreted exosomes

Abstract

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 (KD = 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.

Graphical abstract: Structural and molecular insight into antibody recognition of dynamic neoepitopes in membrane tethered MUC1 of pancreatic cancer cells and secreted exosomes

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Article information

Article type
Paper
Submitted
23 Нау. 2023
Accepted
19 Мам. 2023
First published
24 Мам. 2023
This article is Open Access
Creative Commons BY license

RSC Chem. Biol., 2023,4, 564-572

Structural and molecular insight into antibody recognition of dynamic neoepitopes in membrane tethered MUC1 of pancreatic cancer cells and secreted exosomes

H. Wakui, Y. Yokoi, C. Horidome, T. Ose, M. Yao, Y. Tanaka, H. Hinou and S. Nishimura, RSC Chem. Biol., 2023, 4, 564 DOI: 10.1039/D3CB00036B

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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