Immature truncated O-glycophenotype of cancer directly induces oncogenic features
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Immature truncated O-glycophenotype of cancer directly induces oncogenic features. / Radhakrishnan, Prakash; Dabelsteen, Sally; Madsen, Frey Brus; Francavilla, Chiara; Kopp, Katharina L; Steentoft, Catharina; Vakhrushev, Sergey Y; Olsen, Jesper V; Hansen, Lars; Bennett, Eric P; Woetmann, Anders; Yin, Guangliang; Chen, Longyun; Song, Haiyan; Bak, Mads; Hlady, Ryan A; Peters, Staci L; Opavsky, Rene; Thode, Christenze; Qvortrup, Klaus; Schjoldager, Katrine Ter-Borch Gram; Clausen, Henrik; Hollingsworth, Michael A; Wandall, Hans H.
I: Proceedings of the National Academy of Sciences of the United States of America, Bind 111, Nr. 39, 12.08.2014, s. e4066-e4077.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Immature truncated O-glycophenotype of cancer directly induces oncogenic features
AU - Radhakrishnan, Prakash
AU - Dabelsteen, Sally
AU - Madsen, Frey Brus
AU - Francavilla, Chiara
AU - Kopp, Katharina L
AU - Steentoft, Catharina
AU - Vakhrushev, Sergey Y
AU - Olsen, Jesper V
AU - Hansen, Lars
AU - Bennett, Eric P
AU - Woetmann, Anders
AU - Yin, Guangliang
AU - Chen, Longyun
AU - Song, Haiyan
AU - Bak, Mads
AU - Hlady, Ryan A
AU - Peters, Staci L
AU - Opavsky, Rene
AU - Thode, Christenze
AU - Qvortrup, Klaus
AU - Schjoldager, Katrine Ter-Borch Gram
AU - Clausen, Henrik
AU - Hollingsworth, Michael A
AU - Wandall, Hans H
PY - 2014/8/12
Y1 - 2014/8/12
N2 - 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.
AB - 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.
U2 - 10.1073/pnas.1406619111
DO - 10.1073/pnas.1406619111
M3 - Journal article
C2 - 25118277
VL - 111
SP - e4066-e4077
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 39
ER -
ID: 120784091