Immature truncated O-glycophenotype of cancer directly induces oncogenic features

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 Ter-Borch Gram Schjoldager; Henrik Clausen; Michael A Hollingsworth; Hans H Wandall

doi:10.1073/pnas.1406619111

Immature truncated O-glycophenotype of cancer directly induces oncogenic features

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 QvortrupKatrine Ter-Borch Gram Schjoldager, Henrik Clausen, Michael A Hollingsworth, Hans H Wandall

156 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Proceedings of the National Academy of Sciences of the United States of America
Vol/bind	111
Udgave nummer	39
Sider (fra-til)	e4066-e4077
Antal sider	10
ISSN	0027-8424
DOI	https://doi.org/10.1073/pnas.1406619111
Status	Udgivet - 30 sep. 2014

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10.1073/pnas.1406619111

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Radhakrishnan, P., Dabelsteen, S., Madsen, F. B., Francavilla, C., Kopp, K. L., Steentoft, C., Vakhrushev, S. Y., Olsen, J. V., Hansen, L., Bennett, E. P., Woetmann, A., Yin, G., Chen, L., Song, H., Bak, M., Hlady, R. A., Peters, S. L., Opavsky, R., Thode, C., ... Wandall, H. H. (2014). Immature truncated O-glycophenotype of cancer directly induces oncogenic features. Proceedings of the National Academy of Sciences of the United States of America, 111(39), e4066-e4077. https://doi.org/10.1073/pnas.1406619111

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-BG , Clausen, H, Hollingsworth, MA & Wandall, HH 2014, 'Immature truncated O-glycophenotype of cancer directly induces oncogenic features', Proceedings of the National Academy of Sciences of the United States of America, bind 111, nr. 39, s. e4066-e4077. https://doi.org/10.1073/pnas.1406619111

@article{0d9da85b48f34dd5ab19028cb5d48514,

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.",

author = "Prakash Radhakrishnan and Sally Dabelsteen and Madsen, {Frey Brus} and Chiara Francavilla and Kopp, {Katharina L} and Catharina Steentoft and Vakhrushev, {Sergey Y} and Olsen, {Jesper V} and Lars Hansen and Bennett, {Eric P} and Anders Woetmann and Guangliang Yin and Longyun Chen and Haiyan Song and Mads Bak and Hlady, {Ryan A} and Peters, {Staci L} and Rene Opavsky and Christenze Thode and Klaus Qvortrup and Schjoldager, {Katrine Ter-Borch Gram} and Henrik Clausen and Hollingsworth, {Michael A} and Wandall, {Hans H}",

year = "2014",

month = sep,

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doi = "10.1073/pnas.1406619111",

language = "English",

volume = "111",

pages = "e4066--e4077",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

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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 - 2014/9/30

Y1 - 2014/9/30

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

SN - 0027-8424

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

IS - 39

ER -

Immature truncated O-glycophenotype of cancer directly induces oncogenic features

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