Organelle Specific O-Glycosylation Drives MMP14 Activation, Tumor Growth, and Metastasis

• Published in: Cancer cell 2017-11, Vol.32 (5), p.639-653.e6
• Main Authors: Nguyen, Anh Tuan, Chia, Joanne, Ros, Manon, Hui, Kam Man, Saltel, Frederic, Bard, Frederic
• Format: Article
• Language: English
• Subjects: Animals; Blotting, Western; Cell Proliferation - genetics; Endoplasmic Reticulum - metabolism; GALA; GALNTs; Gene Expression Regulation, Neoplastic; Glycosylation; Golgi Apparatus - metabolism; Hep G2 Cells; Humans; invasion; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Male; Matrix Metalloproteinase 14 - genetics; Matrix Metalloproteinase 14 - metabolism; membrane trafficking; metastasis; Mice, Inbred C57BL; MMP14; MT1-MMP; N-Acetylgalactosaminyltransferases - genetics; N-Acetylgalactosaminyltransferases - metabolism; Neoplasm Metastasis; O-glycosylation; Polypeptide N-acetylgalactosaminyltransferase; Reverse Transcriptase Polymerase Chain Reaction; Tn antigen; tumor growth
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2017.10.001

Cancers grow within tissues through molecular mechanisms still unclear. Invasiveness correlates with perturbed O-glycosylation, a covalent modification of cell-surface proteins. Here, we show that, in human and mouse liver cancers, initiation of O-glycosylation by the GALNT glycosyl-transferases increases and shifts from the Golgi to the endoplasmic reticulum (ER). In a mouse liver cancer model, expressing an ER-targeted GALNT1 (ER-G1) massively increased tumor expansion, with median survival reduced from 23 to 10 weeks. In vitro cell growth was unaffected, but ER-G1 strongly enabled matrix degradation and tissue invasion. Unlike its Golgi-localized counterpart, ER-G1 glycosylates the matrix metalloproteinase MMP14, a process required for tumor expansion. Together, our results indicate that GALNTs strongly promote liver tumor growth after relocating to the ER. [Display omitted] •Malignancy in liver tumors strongly increases ER O-glycosylation•ER-targeted GALNT1 recapitulates advanced tumor stage glycosylation pattern•ER-GALNT1 expressing tumors grow twice faster and invade surrounding organs•ER glycosylation of MMP14 is required for ECM degradation and tumor growth Nguyen et al. find that O-glycosylation increases during liver tumor progression, with increased expression of GALNT1 and glycosylation of ER-associated proteins. In mouse models, expression of GALNT1 in the ER, but not the Golgi, accelerates tumorigenesis and increases invasion through glycosylation of MMP14.