Analysis of the glyco-code in pancreatic ductal adenocarcinoma identifies glycan-mediated immune regulatory circuits
Rodriguez, Ernesto; Boelaars, Kelly; Brown, Kari; Madunić, Katarina; van Ee, Thomas; Dijk, Frederike; Verheij, Joanne; Li, R. J.Eveline; Schetters, Sjoerd T.T.; Meijer, Laura L.; Le Large, Tessa Y.S.; Driehuis, Else; Clevers, Hans; Bruijns, Sven C.M.; O’Toole, Tom; van Vliet, Sandra J.; Bijlsma, Maarten F.; Wuhrer, Manfred; Kazemier, Geert; Giovannetti, Elisa; Garcia-Vallejo, Juan J.; van Kooyk, Yvette
(2022) Communications biology, volume 5, issue 1, pp. 1 - 15
(Article)
Abstract
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
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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.
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Keywords: General Agricultural and Biological Sciences, General Biochemistry,Genetics and Molecular Biology, Medicine (miscellaneous), Research Support, Non-U.S. Gov't, Journal Article
ISSN: 2399-3642
Publisher: Springer Nature
Note: Funding Information: A significant amount of the results in this paper is based on the transcriptomic analysis of publicly available datasets. We would like to acknowledge the work of the research groups responsible for the generation and processing of the datasets used in this paper. We would like to thank Dr. Eduardo Osinaga and Dr. Teresa Freire (Facultad de Medicina, Universidad de la Republica, Uruguay) for their generosity in providing the antibodies 83D4 and B72.3. We also acknowledge the Microscopy and Cytometry Core Facility at the Amsterdam UMC (Location VUmc) for providing assistance in cytometry and microscopy experiments. E.R. is supported by Immu-noshape (MSCA-ITN-2014-ETN No 642870) and Spinoza grant. S.T.T.S. and Y.v.K. are supported by the European Research Council (ERC-339977-Glycotreat). K.Bo. is supported by KWF VU2014-7200. Publisher Copyright: © 2022, The Author(s).
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