Metastasis of cholangiocarcinoma is promoted by extended high-mannose glycans
Menée in vitro et à l'aide d'un modèle murin, cette étude met en évidence le rôle des glycanes à longue chaîne riche en mannoses dans le processus métastatique des cholangiocarcinomes
Cells assemble a dense layer composed of glycans on the plasma membrane, following nontemplated processes that can be perturbed during malignancy. The intrinsic heterogeneity of glycosylation presents challenges to unambiguously identifying disease-specific transformations and selectively targeting them while preventing off-target events. Here, we show that extended high-mannose glycans are more abundantly expressed in metastatic cholangiocarcinoma than in the parental tumor cells from which they were derived. With structure-guided manipulations, extended high-mannose glycans were implicated in supporting cholangiocarcinoma metastasis by enhancing the ability to translocate, invade surrounding basement membrane matrix, and migrate through micropores. Isolation of high-mannose–bearing glycoproteins and computational modeling suggested that dominance of extended high-mannose glycosylation drives metastatic progression by indirectly strengthening extracellular protein complexes.Membrane-bound oligosaccharides form the interfacial boundary between the cell and its environment, mediating processes such as adhesion and signaling. These structures can undergo dynamic changes in composition and expression based on cell type, external stimuli, and genetic factors. Glycosylation, therefore, is a promising target of therapeutic interventions for presently incurable forms of advanced cancer. Here, we show that cholangiocarcinoma metastasis is characterized by down-regulation of the Golgi α-mannosidase I coding gene MAN1A1, leading to elevation of extended high-mannose glycans with terminating α-1,2-mannose residues. Subsequent reshaping of the glycome by inhibiting α-mannosidase I resulted in significantly higher migratory and invasive capabilities while masking cell surface mannosylation suppressed metastasis-related phenotypes. Exclusive elucidation of differentially expressed membrane glycoproteins and molecular modeling suggested that extended high-mannose glycosylation at the helical domain of transferrin receptor protein 1 promotes conformational changes that improve noncovalent interaction energies and lead to enhancement of cell migration in metastatic cholangiocarcinoma. The results provide support that α-1,2-mannosylated N-glycans present on cancer cell membrane proteins may serve as therapeutic targets for preventing metastasis.