The transcriptional landscape of glycosylation-related genes in cancer

Abstract

Changes in glycosylation patterns have been associated with malignant transformation and clinical outcome in several types of cancer, although no comprehensive analysis has been performed in a pan-cancer setting. Here, we performed an extensive transcriptomic analysis of glycosylation related genes (such as enzymes involved in synthesis and degradation of glycoconjugates, transporters, mucins and galectins), using publicly available bulk and single cell transcriptomic data sets from tumor samples and cancer cell lines. We identified genes and pathways associated with different tumor types, which may represent novel diagnostic biomarkers as α2-3 sialylation for Melanoma, MUC21 for Lung adenocarcinoma and Galectin-7 for Squamous cell carcinomas (SCC). Accordingly, serum levels of Galectin-7 in patients with lung cancer were elevated in SCC respect to adenocarcinomas, supporting its biomarker potential. Moreover, we characterized the contribution of different cell types to the overall glycosylation profiles observed by performing the integration and analysis of 14 single cell RNA-seq datasets. This led us to identify that cancer cells are responsible for the specific tumor glyco-codes identified in bulk transcriptomics, while stromal and immune cells contribute in a conserved manner across various malignancies. Furthermore, our results suggest that the glycosylation-related genes and pathways expressed by cancer cells are influenced by the cell of origin and the oncogenic pathways that led to malignant transformation. Lastly, we described the association of different glycosylation-related genes and pathways with the clinical outcome of patients. Interestingly, while the expression of genes associated to some pathways (as proteoglycan biosynthesis) are consistently associated with a more aggressive disease, the correlation of others pathways with the survival of patients depends on the particular tumor type. Remarkably, the expression of genes associated with the synthesis of CMP-sialic acid was correlated with lower survival of patients in Uveal Melanoma and PDAC, while the opposite was observed for colorectal cancer. The extensive transcriptomic analysis of glycosylation pathways in cancer that we report here can serve as a resource for future research aimed to unravel the glyco-code in cancer related to clinical outcome or biomarker development.

Pancreatic cancer-associated fibroblasts modulate macrophage differentiation via sialic acid-Siglec interactions

“…In addition, ST3GAL4 is related to an increased invasive phenotype in tumor cells as it generates the glycan sialyl-Lewis X, which facilitates cell adhesion 72,73 . Interestingly, recent studies also observed increased ST3GAL4 expression in the stroma in other cancer types, including colorectal, lung, cervical and esophageal cancer 67,74 . Stromal sialylation therefore likely plays a role in other cancer types as well.…”

“…For identification of CAF subtypes, cells were reclustered as described before but using a resolution of 0.25. The function AddModuleScore was employed to generate gene scores for different glycosylation pathways using genesets previously described 74 (supplementary Table 3). The scripts used in this manuscript for the analysis of scRNA-Seq can be found in https://github.com/MolecularCellBiologyImmunology/ Sialylation_CAF.…”

Limited impact of cancer-derived gangliosides on anti-tumor immunity in colorectal cancer

“…In conclusion, we demonstrate that the contribution of only ST3Gal5 on anti-tumor immunity is modest. Nevertheless, in combination with other sialyltransferases, the effect of glycan-dependent immune evasion might be larger, since it is not one single modification, but multiple glycosylation changes occurring in each tumor type ( Rodriguez et al. 2022 ).…”