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 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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive malignancies with a 5-year survival rate of only 9%
Changes in glycosylated structures during malignant transformation have been widely reported in the literature over the last decades, highlighting the role of a diverse array of glycans in cancer progression depending on the tumour type, stage or grading[8]. This is the case in PDAC, where different glycan structures or glycoproteins are used for diagnostics or have been proposed as targets in therapeutic approaches[10,35,36]
The analysis of transcriptomic data of datasets of tissue samples from patients, and the subsequent validation in PDAC tissues, organoids and cell lines, allowed us to identify two glycocode dependent subtypes of cancer cells, that can be discriminated by the presence of fucosylated antigens
Summary
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive malignancies with a 5-year survival rate of only 9%. 1234567890():,; Pancreatic ductal adenocarcinoma (PDAC) represents one of the most aggressive malignancies, with a 5-year survival rate of only 9% and predicted to become the second leading cause of cancer-related deaths in the United States[1,2] This is mainly a reflection of late diagnosis, as many patients present with surgically unresectable tumours, and a lack of other effective therapies[1,3]. Because immune cells express a large variety of glycan-binding receptors (called lectins), such as C-type lectins (DC-SIGN, MR and MGL), Siglecs and galectins, they can sense and respond to changes in the glycan signature of their environment; which often leads to the induction of inhibitory immune processes in those cells[8,9] It is unclear which glycan signatures present in PDAC are able to interact with immune cells and contribute to the tolerogenic TME. A better understanding of glycan expression profiles may provide new insights into mechanisms of immune escape
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