Organelle Specific O-Glycosylation Drives MMP14 Activation, Tumor Growth, and Metastasis
Menée in vitro et in vivo sur des modèles de cancer du foie, cette étude met en évidence des mécanismes par lesquels une glycosylation de la métalloprotéase matricielle MMP14 sur le réticulum endoplasmique favorise la croissance tumorale et le processus métastatique
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.