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.
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.