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

Author(s): Radhakrishnan P,  Dabelsteen S,  Madsen FB,  Francavilla C,  Kopp KL,  Steentoft C,  Vakhrushev SY,  Olsen JV,  Hansen L,  Bennett EP,  Woetmann A,  Yin G,  Chen L,  Song H,  Bak M,  Hlady RA,  Peters SL,  Opavsky R,  Thode C,  Qvortrup K,  Schjoldager KT,  Clausen H,  Hollingsworth MA,  Wandall HH

Journal: Proc Natl Acad Sci U S A

Date: 2014 Sep 30

Major Program(s) or Research Group(s): GLYCO

PubMed ID: 25118277

PMC ID: PMC4191756

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.