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  current news   Press   selected story    
     
  19 August 2013  
  Initiation of O-GalNAc glycosylation in the endoplasmic reticulum promotes cancer cell invasiveness
 
 



Authors
David J. Gilla, Keit Min Thama, Keit Min Thama, Joanne Chiaa, Shyi Chyi Wanga, Catharina Steentoftb, Henrik Clausenb, Emilie A. Bard-Chapeaua and Frederic A. Barda,c

a - Institute of Molecular and Cell Biology, Proteos, Singapore 138673      
b - Department of Cellular and Molecular Medicine, Copenhagen Center for Glycomics,
     University of Copenhagen, Denmark
c - Department of Biochemistry, National University of Singapore, Singapore 119077

Published in PNAS on 29 July 2013.

Abstract

Invasiveness underlies cancer aggressiveness and is a hallmark of malignancy. Most malignant tumors have elevated levels of Tn, an O-GalNAc glycan. Mechanisms underlying Tn up-regulation and its effects remain unclear. Here we show that Golgi-to-endoplasmic reticulum relocation of polypeptide N-acetylgalactosaminetransferases (GalNAc-Ts) drives high Tn levels in cancer cell lines and in 70% of malignant breast tumors. This process stimulates cell adhesion to the extracellular matrix, as well as migration and invasiveness. The GalNAc-Ts lectin domain, mediating high-density glycosylation, is critical for these effects. Interfering with the lectin domain function inhibited carcinoma cell migration in vitro and metastatic potential in mice. We also show that stimulation of cell migration is dependent Tn-bearing proteins present in lamellipodia of migrating cells. Our findings suggest that relocation of GalNAc- Ts to the endoplasmic reticulum frequently occurs upon cancerous transformation to enhance tumor cell migration and invasiveness through modification of cell surface proteins.

Figure legend: Inhibiting Endoplasmic Reticulum (ER) localized O-glycosylation dramatically reduces the formation of lung metastasis.

Mice were injected intravenously with mammary tumor cells of the 4T1 line  expressing either a GFP targeted to the ER (Left) or an inhibitor of O-glycosylation called 2Lec also targeted to the ER (Right).



For more information on Frederic BARD's laboratory, please click here.