Truncated O-glycans promote epithelial-to-mesenchymal transition and stemness properties of pancreatic cancer cells

Divya Thomas; Satish Sagar; Thomas Caffrey; Paul M. Grandgenett; Prakash Radhakrishnan

doi:10.1111/jcmm.14572

Truncated O-glycans promote epithelial-to-mesenchymal transition and stemness properties of pancreatic cancer cells

Divya Thomas, Satish Sagar, Thomas Caffrey, Paul M. Grandgenett, Prakash Radhakrishnan

Research output: Contribution to journal › Article › peer-review

32 Scopus citations

Abstract

Aberrant expression of Sialyl-Tn (STn) antigen correlates with poor prognosis and reduced patient survival. We demonstrated that expression of Tn and STn in pancreatic ductal adenocarcinoma (PDAC) is due to hypermethylation of Core 1 synthase specific molecular chaperone (COSMC) and enhanced the malignant properties of PDAC cells with an unknown mechanism. To explore the mechanism, we have genetically deleted COSMC in PDAC cells to express truncated O-glycans (SimpleCells, SC) which enhanced cell migration and invasion. Since epithelial-to-mesenchymal transition (EMT) play a vital role in metastasis, we have analysed the induction of EMT in SC cells. Expressions of the mesenchymal markers were significantly high in SC cells as compared to WT cells. Equally, we found reduced expressions of the epithelial markers in SC cells. Re-expression of COSMC in SC cells reversed the induction of EMT. In addition to this, we also observed an increased cancer stem cell population in SC cells. Furthermore, orthotopic implantation of T3M4 SC cells into athymic nude mice resulted in significantly larger tumours and reduced animal survival. Altogether, these results suggest that aberrant expression of truncated O-glycans in PDAC cells enhances the tumour aggressiveness through the induction of EMT and stemness properties.

Original language	English (US)
Pages (from-to)	6885-6896
Number of pages	12
Journal	Journal of cellular and molecular medicine
Volume	23
Issue number	10
DOIs	https://doi.org/10.1111/jcmm.14572
State	Published - Oct 1 2019

Keywords

COSMC
EMT
PDAC
core-1 synthase
stem cells
truncated O-glycans

ASJC Scopus subject areas

Molecular Medicine
Cell Biology

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10.1111/jcmm.14572

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@article{9ce8a021ace341d0a65f1bfbecd03480,

title = "Truncated O-glycans promote epithelial-to-mesenchymal transition and stemness properties of pancreatic cancer cells",

abstract = "Aberrant expression of Sialyl-Tn (STn) antigen correlates with poor prognosis and reduced patient survival. We demonstrated that expression of Tn and STn in pancreatic ductal adenocarcinoma (PDAC) is due to hypermethylation of Core 1 synthase specific molecular chaperone (COSMC) and enhanced the malignant properties of PDAC cells with an unknown mechanism. To explore the mechanism, we have genetically deleted COSMC in PDAC cells to express truncated O-glycans (SimpleCells, SC) which enhanced cell migration and invasion. Since epithelial-to-mesenchymal transition (EMT) play a vital role in metastasis, we have analysed the induction of EMT in SC cells. Expressions of the mesenchymal markers were significantly high in SC cells as compared to WT cells. Equally, we found reduced expressions of the epithelial markers in SC cells. Re-expression of COSMC in SC cells reversed the induction of EMT. In addition to this, we also observed an increased cancer stem cell population in SC cells. Furthermore, orthotopic implantation of T3M4 SC cells into athymic nude mice resulted in significantly larger tumours and reduced animal survival. Altogether, these results suggest that aberrant expression of truncated O-glycans in PDAC cells enhances the tumour aggressiveness through the induction of EMT and stemness properties.",

keywords = "COSMC, EMT, PDAC, core-1 synthase, stem cells, truncated O-glycans",

author = "Divya Thomas and Satish Sagar and Thomas Caffrey and Grandgenett, {Paul M.} and Prakash Radhakrishnan",

note = "Funding Information: This work was supported in part by National Cancer Institute (NCI/NIH) grant (R01CA208108-01A1), NIH/SPORE Career Development Award (P50CA127297), NE-DHHS/LB506, and Eppley Institute for Research in Cancer and Allied Diseases start-up fund, and by the Fred and Pamela Buffet Cancer Center grants (U01CA210240, P30CA36727 and R50CA211462). We thank Dr Michael A. Hollingsworth (University of Nebraska Medical Center) for providing reagents. We also thank Drs Henrik Clausen and Catherina Steentoft (University of Copenhagen, Denmark) for providing PDAC SimpleCells. Publisher Copyright: {\textcopyright} 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.",

year = "2019",

month = oct,

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doi = "10.1111/jcmm.14572",

language = "English (US)",

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T1 - Truncated O-glycans promote epithelial-to-mesenchymal transition and stemness properties of pancreatic cancer cells

AU - Thomas, Divya

AU - Sagar, Satish

AU - Caffrey, Thomas

AU - Grandgenett, Paul M.

AU - Radhakrishnan, Prakash

N1 - Funding Information: This work was supported in part by National Cancer Institute (NCI/NIH) grant (R01CA208108-01A1), NIH/SPORE Career Development Award (P50CA127297), NE-DHHS/LB506, and Eppley Institute for Research in Cancer and Allied Diseases start-up fund, and by the Fred and Pamela Buffet Cancer Center grants (U01CA210240, P30CA36727 and R50CA211462). We thank Dr Michael A. Hollingsworth (University of Nebraska Medical Center) for providing reagents. We also thank Drs Henrik Clausen and Catherina Steentoft (University of Copenhagen, Denmark) for providing PDAC SimpleCells. Publisher Copyright: © 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

PY - 2019/10/1

Y1 - 2019/10/1

N2 - Aberrant expression of Sialyl-Tn (STn) antigen correlates with poor prognosis and reduced patient survival. We demonstrated that expression of Tn and STn in pancreatic ductal adenocarcinoma (PDAC) is due to hypermethylation of Core 1 synthase specific molecular chaperone (COSMC) and enhanced the malignant properties of PDAC cells with an unknown mechanism. To explore the mechanism, we have genetically deleted COSMC in PDAC cells to express truncated O-glycans (SimpleCells, SC) which enhanced cell migration and invasion. Since epithelial-to-mesenchymal transition (EMT) play a vital role in metastasis, we have analysed the induction of EMT in SC cells. Expressions of the mesenchymal markers were significantly high in SC cells as compared to WT cells. Equally, we found reduced expressions of the epithelial markers in SC cells. Re-expression of COSMC in SC cells reversed the induction of EMT. In addition to this, we also observed an increased cancer stem cell population in SC cells. Furthermore, orthotopic implantation of T3M4 SC cells into athymic nude mice resulted in significantly larger tumours and reduced animal survival. Altogether, these results suggest that aberrant expression of truncated O-glycans in PDAC cells enhances the tumour aggressiveness through the induction of EMT and stemness properties.

AB - Aberrant expression of Sialyl-Tn (STn) antigen correlates with poor prognosis and reduced patient survival. We demonstrated that expression of Tn and STn in pancreatic ductal adenocarcinoma (PDAC) is due to hypermethylation of Core 1 synthase specific molecular chaperone (COSMC) and enhanced the malignant properties of PDAC cells with an unknown mechanism. To explore the mechanism, we have genetically deleted COSMC in PDAC cells to express truncated O-glycans (SimpleCells, SC) which enhanced cell migration and invasion. Since epithelial-to-mesenchymal transition (EMT) play a vital role in metastasis, we have analysed the induction of EMT in SC cells. Expressions of the mesenchymal markers were significantly high in SC cells as compared to WT cells. Equally, we found reduced expressions of the epithelial markers in SC cells. Re-expression of COSMC in SC cells reversed the induction of EMT. In addition to this, we also observed an increased cancer stem cell population in SC cells. Furthermore, orthotopic implantation of T3M4 SC cells into athymic nude mice resulted in significantly larger tumours and reduced animal survival. Altogether, these results suggest that aberrant expression of truncated O-glycans in PDAC cells enhances the tumour aggressiveness through the induction of EMT and stemness properties.

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KW - PDAC

KW - core-1 synthase

KW - stem cells

KW - truncated O-glycans

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Truncated O-glycans promote epithelial-to-mesenchymal transition and stemness properties of pancreatic cancer cells

Abstract

Keywords

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