Immature truncated O-glycophenotype of cancer directly induces oncogenic features

Research output: Contribution to journalJournal articleResearchpeer-review

  • Prakash Radhakrishnan
  • Frey Brus Madsen
  • Chiara Francavilla
  • Katharina L Kopp
  • Catharina Steentoft
  • Guangliang Yin
  • Longyun Chen
  • Haiyan Song
  • Mads Bak
  • Ryan A Hlady
  • Staci L Peters
  • Rene Opavsky
  • Christenze Thode
  • Michael A Hollingsworth

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.

Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number39
Pages (from-to)e4066-e4077
Number of pages10
Publication statusPublished - 12 Aug 2014

ID: 120784091