Metastasis of cholangiocarcinoma is promoted by extended high-mannose glycans

Diane Dayoung Park, Chatchai Phoomak, Gege Xu, Laura P. Olney, Khiem A. Tran, Simon S. Park, Nathan E. Haigh, Guillaume Luxardi, Worachart Lert-Itthiporn, Michiko Shimoda, Qiongyu Li, Nobuyuki Matoba, Fernando Fierro, Sopit Wongkham, Emanual Maverakis, Carlito B. Lebrilla

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Membrane-bound oligosaccharides form the interfacial boundary between the cell and its environment, mediating processes such as adhesion and signaling. These structures can undergo dynamic changes in composition and expression based on cell type, external stimuli, and genetic factors. Glycosylation, therefore, is a promising target of therapeutic interventions for presently incurable forms of advanced cancer. Here, we show that cholangiocarcinoma metastasis is characterized by down-regulation of the Golgi α-mannosidase I coding gene MAN1A1, leading to elevation of extended high-mannose glycans with terminating α-1,2-mannose residues. Subsequent reshaping of the glycome by inhibiting α-mannosidase I resulted in significantly higher migratory and invasive capabilities while masking cell surface mannosylation suppressed metastasis-related phenotypes. Exclusive elucidation of differentially expressed membrane glycoproteins and molecular modeling suggested that extended high-mannose glycosylation at the helical domain of transferrin receptor protein 1 promotes conformational changes that improve noncovalent interaction energies and lead to enhancement of cell migration in metastatic cholangiocarcinoma. The results provide support that α-1,2-mannosylated N-glycans present on cancer cell membrane proteins may serve as therapeutic targets for preventing metastasis.

Original languageEnglish (US)
Pages (from-to)7633-7644
Number of pages12
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number14
DOIs
StatePublished - Apr 7 2020

Keywords

  • Cholangiocarcinoma
  • Glycosylation
  • Mass spectrometry
  • Membrane proteins
  • Metastasis

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Metastasis of cholangiocarcinoma is promoted by extended high-mannose glycans'. Together they form a unique fingerprint.

  • Cite this

    Park, D. D., Phoomak, C., Xu, G., Olney, L. P., Tran, K. A., Park, S. S., Haigh, N. E., Luxardi, G., Lert-Itthiporn, W., Shimoda, M., Li, Q., Matoba, N., Fierro, F., Wongkham, S., Maverakis, E., & Lebrilla, C. B. (2020). Metastasis of cholangiocarcinoma is promoted by extended high-mannose glycans. Proceedings of the National Academy of Sciences of the United States of America, 117(14), 7633-7644. https://doi.org/10.1073/pnas.1916498117