Anh Tuan NGUYEN1,6, Joanne CHIA1,6, Manon ROS1, Kam Man HUI1,2,3,4, Frederic Saltel5 and Frederic BARD1,2
1 Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673
2 Department of Biochemistry, National University of Singapore, 21 Lower Kent Ridge Road, Singapore 119077
3 Division of Cellular and Molecular Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610
4 Duke-NUS Graduate Medical School, Singapore, 8 College Road, Singapore 169857
5 INSERM, U1053 Bordeaux Research In Translational Oncology, BaRITOn, F-33000 Bordeaux, France; Univ. Bordeaux, U1053 Bordeaux Research In Translational Oncology, BaRITOn, F-33000 Bordeaux, France
6 These authors contributed equally
Published in Cancer Cell on 13 November 2017.
The Sweet Jaws of Cancer:
In the human body, cell coordination relies heavily on complex sugars attached to cell surface proteins. These sugars regulate how cells maintain tissue integrity. How this sugar-based coordination system is regulated is still poorly understood and it is not known whether and how cancer cells subvert it. In the Fred Bard lab, we are interested in the mechanisms of regulation of cell surface sugars. These sugars are added in a series of intracellular compartments that ressemble an assembly line. We found that this assembly line is dynamic and can be re-modelled upon activation of signalling cascades. In this study, we show liver cancer cells re-organise their O-GalNAc sugar assembly line, resulting in a massive up-regulation of GalNac addition. This process allows liver tumors to grow within the normal tissue. Sugar coupling to the molecular scissor protein called MMP14 strongly activates it. This confers cancer cells the ability to chew through the ExtraCellular Matrix of normal tissue, ultimately allowing tumors to gain space at the expense of normal cells. This sugar-based activation process, which we coined the GALA pathway, occurs in nine out of ten of human liver cancers and appears to be involved in other solid tumors, opening a new angle of attack against cancer.
Figure legend: Top panel: In normal cells, O-GalNAc glycosylation on proteins occurs in the Golgi apparatus. The initiating step of this process is catalysed by the GALNTs glycosyltransferases that adds a GalNAc sugar to a serine/theonine residue on the protein. The O-glycan is sequentially extended by other glycosyltransferases as the glycoprotein traverses through the Golgi. Bottom panel: Relocation of GALNT to the ER, also known as GALA, augments O-glycosylation on multiple proteins including matrix metalloproteinase MMP14 and also glycosylates ER resident proteins that are normally not O-glycosylated. Increased glycosylation on MMP14 enhances its activity and thus potentiating extracellular matrix degradation, tumor growth and invasiveness.
For more information on Frederic BARD 's lab, please click here.