Analysis of the glyco-code in pancreatic ductal adenocarcinoma identifies glycan-mediated immune regulatory circuits

Rodriguez, E.; Boelaars, K.; Brown, K.; Madunic, K.; Ee, T. van; Dijk, F.; Verheij, J.; Li, R.J.E.; Schetters, S.T.T.; Meijer, L.L.; Large, T.Y.S. le; Driehuis, E.; Clevers, H.; Bruijns, S.C.M.; O'Toole, T.; Vliet, S.J. van; Bijlsma, M.F.; Wuhrer, M.; Kazemier, G.; Giovannetti, E.; Garcia-Vallejo, J.J.; Kooyk, Y. van

doi:doi:10.1038/s42003-021-02934-0

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive malignancies with a 5-year survival rate of only 9%. Despite the fact that changes in glycosylation patterns during tumour progression have been reported, no systematic approach has been conducted to evaluate its potential for patient stratification. By analysing publicly available transcriptomic data of patient samples and cell lines, we identified here two specific glycan profiles in PDAC that correlated with progression, clinical outcome and epithelial to mesenchymal transition (EMT) status. These different glycan profiles, confirmed by glycomics, can be distinguished by the expression of O-glycan fucosylated structures, present only in epithelial cells and regulated by the expression of GALNT3. Moreover, these fucosylated glycans can serve as ligands for DC-SIGN positive tumour-associated macrophages, modulating their activation and inducing the production of IL-10. Our results show mechanisms by which...Show morePancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive malignancies with a 5-year survival rate of only 9%. Despite the fact that changes in glycosylation patterns during tumour progression have been reported, no systematic approach has been conducted to evaluate its potential for patient stratification. By analysing publicly available transcriptomic data of patient samples and cell lines, we identified here two specific glycan profiles in PDAC that correlated with progression, clinical outcome and epithelial to mesenchymal transition (EMT) status. These different glycan profiles, confirmed by glycomics, can be distinguished by the expression of O-glycan fucosylated structures, present only in epithelial cells and regulated by the expression of GALNT3. Moreover, these fucosylated glycans can serve as ligands for DC-SIGN positive tumour-associated macrophages, modulating their activation and inducing the production of IL-10. Our results show mechanisms by which the glyco-code contributes to the tolerogenic microenvironment in PDAC.Rodriguez et al. present a transcriptomic analysis of glycosylation associated gene profiles, including bulk patient sequencing, sc-RNA seq, cell lines and organoids, to examine glycosylation in PDAC. They find 2 specific glycan profiles correlating with progression, clinical outcome and EMT, and conclude that the glyco-code contributes to the tolerogenic microenvironment in PDAC.Show less

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Analysis of the glyco-code in pancreatic ductal adenocarcinoma identifies glycan-mediated immune regulatory circuits