Metastasis of cholangiocarcinoma is promoted by extended high-mannose glycans
Dayoung Park, Chatchai Phoomak, Gege Xu, Laura Olney, Khiem A. Tran, Simon Park, Nathan E. Haigh, Guillaume Luxardi, Worachart Lert-itthiporn, Michiko Shimoda, Qiongyu Li, Nobuyuki Matoba, Fernando A. Fierro, Sopit Wongkham, Emanual Maverakis, Carlito B. Lebrilla
Abstract
Significance 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.