title: 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.affiliation: Eppley Institute for Research in Cancer, Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-5950;
authors.forename: Prakash
authors.initials: P
authors.lastname: Radhakrishnan
authors.affiliation: Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Department of Pathology and Medicine, School of Dentistry.
authors.forename: Sally
authors.initials: S
authors.lastname: Dabelsteen
authors.affiliation: Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Department of Pathology and Medicine, School of Dentistry.
authors.forename: Frey Brus
authors.initials: FB
authors.lastname: Madsen
authors.affiliation: Protein Center.
authors.forename: Chiara
authors.initials: C
authors.lastname: Francavilla
authors.affiliation: Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine.
authors.forename: Katharina L
authors.initials: KL
authors.lastname: Kopp
authors.affiliation: Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine.
authors.forename: Catharina
authors.initials: C
authors.lastname: Steentoft
authors.affiliation: Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine.
authors.forename: Sergey Y
authors.initials: SY
authors.lastname: Vakhrushev
authors.affiliation: Protein Center.
authors.forename: Jesper V
authors.initials: JV
authors.lastname: Olsen
authors.affiliation: Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine.
authors.forename: Lars
authors.initials: L
authors.lastname: Hansen
authors.affiliation: Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Bennett
authors.affiliation: Department of Immunology, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark; and.
authors.forename: Anders
authors.initials: A
authors.lastname: Woetmann
authors.affiliation: BGI-Tech, BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Guangliang
authors.initials: G
authors.lastname: Yin
authors.affiliation: BGI-Tech, BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Longyun
authors.initials: L
authors.lastname: Chen
authors.affiliation: BGI-Tech, BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Song
authors.affiliation: Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine.
authors.forename: Mads
authors.initials: M
authors.lastname: Bak
authors.affiliation: Eppley Institute for Research in Cancer, Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-5950;
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Hlady
authors.affiliation: Eppley Institute for Research in Cancer, Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-5950;
authors.forename: Staci L
authors.initials: SL
authors.lastname: Peters
authors.affiliation: Eppley Institute for Research in Cancer, Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-5950;
authors.forename: Rene
authors.initials: R
authors.lastname: Opavsky
authors.affiliation: Department of Pathology and Medicine, School of Dentistry.
authors.forename: Christenze
authors.initials: C
authors.lastname: Thode
authors.affiliation: Department of Biomedical Sciences/Core Facility for Integrated Microscopy, and.
authors.forename: Klaus
authors.initials: K
authors.lastname: Qvortrup
authors.affiliation: Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine.
authors.forename: Katrine T-B G
authors.initials: KT
authors.lastname: Schjoldager
authors.affiliation: Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine.
authors.forename: Henrik
authors.initials: H
authors.lastname: Clausen
authors.affiliation: Eppley Institute for Research in Cancer, Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-5950;
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hollingsworth
authors.affiliation: Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, hhw@sund.ku.dk.
authors.forename: Hans H
authors.initials: HH
authors.lastname: Wandall
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D059472:Exome / Q000235:genetics; D054794:Glycomics; D006031:Glycosylation; D064593:Heterografts; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D016513:Mice, SCID; D018832:Molecular Chaperones / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D011134:Polysaccharides / Q000737:chemistry* / Q000378:metabolism*; D040901:Proteomics; D015398:Signal Transduction
chemical_list: C505369:C1GALT1C1 protein, human; D018832:Molecular Chaperones; D011134:Polysaccharides
keywords: epigenetics; glycans; keratinocyte; pancreas; skin