Roles of glycosylation at the cancer cell surface: opportunities for large scale glycoproteomics

Abstract

Cell surface glycosylation has a variety of functions, and its dysregulation in cancer contributes to impaired signaling, metastasis and the evasion of the immune responses. Recently, a number of glycosyltransferases that lead to altered glycosylation have been linked to reduced anti-tumor immune responses: B3GNT3, which is implicated in PD-L1 glycosylation in triple negative breast cancer, FUT8, through fucosylation of B7H3, and B3GNT2, which confers cancer resistance to T cell cytotoxicity. Given the increased appreciation of the relevance of protein glycosylation, there is a critical need for the development of methods that allow for an unbiased interrogation of cell surface glycosylation status.Here we provide an overview of the broad changes in glycosylation at the surface of cancer cell and describe selected examples of receptors with aberrant glycosylation leading to functional changes, with emphasis on immune checkpoint inhibitors, growth-promoting and growth-arresting receptors. Finally, we posit that the field of glycoproteomics has matured to an extent where large-scale profiling of intact glycopeptides from the cell surface is feasible and is poised for discovery of new actionable targets against cancer.

Pyridinium-Based Strategy for a Bioorthogonal Conjugation-Assisted Purification Method for Profiling Cell Surface Proteome

“…Therefore, conducting a comprehensive analysis of CSPs for targeted therapy, immunotherapy, and vaccine development . Surface proteome studies are crucial for understanding the diversity and function of cell surface proteins. − Recent studies have utilized advanced techniques to identify and quantify cell surface proteins in different cell types, including immune and cancer cells . These studies have significant implications for targeted therapy, immunotherapy, and vaccine development .…”

Sensitive and Specific Global Cell Surface N-Glycoproteomics Shows Profound Differences Between Glycosylation Sites and Subcellular Components

“…Importantly, not only can N -glycosylation be targeted with the current approach, but also different types of O -linked glycosylation have high potential to benefit from the improved sensitivity and specificity using the introduced enrichment strategy. We expect the applicability of the method in a wide array of glycobiological questions, of which a prominent one is the identification of cancer-specific carbohydrate epitopes present at the cell surface …”

“…Furthermore, it will advance the discovery of relevant glycoforms for drug targeting. 16 ■ EXPERIMENTAL SECTION Total Cell Collection. After cell culture (see Supporting Experimental Section), the keratinocytes were washed twice with ambient PBS and harvested by scraping in PBS.…”

“…The method will be an essential component of future cellular glycoproteomic analyses and provides new knowledge that will increase our understanding of contextual glycan functions, such as the discrimination between healthy and diseased cells by our immune system. Furthermore, it will advance the discovery of relevant glycoforms for drug targeting …”

Dielectrophoretic Capture of Cancer‐Derived Small‐Extracellular‐Vesicle‐Bound Janus Nanoparticles via Lectin–Glycan Interaction

“…[ 26 ] This characteristic glycosylation pattern of α2–6‐sialylation, α1–3‐fucosylation, or α1–6‐fucosylation, could provide valuable clues for the diagnosis/prognosis of pancreatic cancer. [ 3,27,28 ] Therefore, glycan‐targeting approaches using glycan‐specific probes could facilitate sEV detection. Lectins (glycan‐binding proteins) could be used to target cancer‐specific glycans for disease diagnosis.…”