Immature truncated O-glycophenotype of cancer directly induces oncogenic features.

Abstract

Aberrant expression of immature truncated O-glycans is a characteristic feature observed on virtually all epithelial cancer cells, and a very high frequency is observed in early epithelial premalignant lesions that precede the development of adenocarcinomas. Expression of the truncated O-glycan structures Tn and sialyl-Tn is strongly associated with poor prognosis and overall low survival. The genetic and biosynthetic mechanisms leading to accumulation of truncated O-glycans are not fully understood and include mutation or dysregulation of glycosyltransferases involved in elongation of O-glycans, as well as relocation of glycosyltransferases controlling initiation of O-glycosylation from Golgi to endoplasmic reticulum. Truncated O-glycans have been proposed to play functional roles for cancer-cell invasiveness, but our understanding of the biological functions of aberrant glycosylation in cancer is still highly limited. Here, we used exome sequencing of most glycosyltransferases in a large series of primary and metastatic pancreatic cancers to rule out somatic mutations as a cause of expression of truncated O-glycans. Instead, we found hypermethylation of core 1 β3-Gal-T-specific molecular chaperone, a key chaperone for O-glycan elongation, as the most prevalent cause. We next used gene editing to produce isogenic cell systems with and without homogenous truncated O-glycans that enabled, to our knowledge, the first polyomic and side-by-side evaluation of the cancer O-glycophenotype in an organotypic tissue model and in xenografts. The results strongly suggest that truncation of O-glycans directly induces oncogenic features of cell growth and invasion. The study provides support for targeting cancer-specific truncated O-glycans with immunotherapeutic measures.

• Authors: Prakash Radhakrishnan, Sally Dabelsteen, Frey Brus Madsen, Chiara Francavilla, Katharina L Kopp, Catharina Steentoft, Sergey Y Vakhrushev, Jesper V Olsen, Lars Hansen, Eric P Bennett, Anders Woetmann, Guangliang Yin, Longyun Chen, Haiyan Song, Mads Bak, Ryan A Hlady, Staci L Peters, Rene Opavsky, Christenze Thode, Klaus Qvortrup, Katrine T-B G Schjoldager, Henrik Clausen, Michael A Hollingsworth, Hans H Wandall
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 39 Pg. E4066-75 (Sep 30 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 25118277 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• C1GALT1C1 protein, human
• Molecular Chaperones
• Polysaccharides

Topics

• Animals
• Cell Adhesion
• Cell Differentiation
• Cell Line, Tumor
• Cell Proliferation
• Exome (genetics)
• Glycomics
• Glycosylation
• Heterografts
• Humans
• Mice
• Mice, Knockout
• Mice, Nude
• Mice, SCID
• Molecular Chaperones (chemistry, genetics, metabolism)
• Mutation
• Neoplasm Invasiveness
• Pancreatic Neoplasms (genetics, metabolism, pathology)
• Phenotype
• Polysaccharides (chemistry, metabolism)
• Proteomics
• Signal Transduction