Tools to study and target the Siglec–sialic acid axis in cancer

Läubli, Heinz; Kawanishi, Kunio; Vazhappilly, Cijo George; Matar, Rachel; Merheb, Maxime; Siddiqui, Shoib Sarwar

doi:10.1111/febs.15647

Cited by 37 publications

(23 citation statements)

References 156 publications

(248 reference statements)

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“…The proper sialylation of mammalian glycoconjugates results from the balanced expressions and activities of sialyltransferases and sialidases involved in attachment or cleavage of sialic acids from the sugar chains of glycolipids and glycoproteins [ 83 ]. In cancer, the aberrant sialylation is closely related to elevated expression of sialyltransferases, including ST3Gal1, STGal4, ST6-Gal1 and ST8Sia2, and their products, especially Sialyl-Levis a,x epitopes that correlate with poor prognosis [ 84 , 85 ]. Indeed, the ST8Sia2-mediated aberrant polysialylation in selected cancers, including glial tumours, is known to negatively regulate the production of pro-inflammatory mediators [ 86 ].…”

Section: Discussionmentioning

confidence: 99%

The Paired Siglecs in Brain Tumours Therapy: The Immunomodulatory Effect of Dexamethasone and Temozolomide in Human Glioma In Vitro Model

Wielgat

Wawrusiewicz‐Kurylonek

Czarnomysy

et al. 2021

IJMS

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The paired sialic acid-binding immunoglobulin like lectins (Siglecs) are characterized by similar cellular distribution and ligand recognition but opposing signalling functions attributed to different intracellular sequences. Since sialic acid—Siglec axis are known to control immune homeostasis, the imbalance between activatory and inhibitory mechanisms of glycan-dependent immune control is considered to promote pathology. The role of sialylation in cancer is described, however, its importance in immune regulation in gliomas is not fully understood. The experimental and clinical observation suggest that dexamethasone (Dex) and temozolomide (TMZ), used in the glioma management, alter the immunity within the tumour microenvironment. Using glioma-microglia/monocytes transwell co-cultures, we investigated modulatory action of Dex/TMZ on paired Siglecs. Based on real-time PCR and flow cytometry, we found changes in SIGLEC genes and their products. These effects were accompanied by altered cytokine profile and immune cells phenotype switching measured by arginases expression. Additionally, the exposure to Dex or TMZ increased the binding of inhibitory Siglec-5 and Siglec-11 fusion proteins to glioma cells. Our study suggests that the therapy-induced modulation of the interplay between sialoglycans and paired Siglecs, dependently on patient’s phenotype, is of particular signification in the immune surveillance in the glioma management and may be useful in glioma patient’s therapy plan verification.

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Section: Discussionmentioning

confidence: 99%

The Paired Siglecs in Brain Tumours Therapy: The Immunomodulatory Effect of Dexamethasone and Temozolomide in Human Glioma In Vitro Model

Wielgat

Wawrusiewicz‐Kurylonek

Czarnomysy

et al. 2021

IJMS

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“…Our previous study developing the new Siglec-Fc scaffold only focused on human Siglecs. 17 Given the striking evolutionary differences between Siglecs in mouse and human, 42,43 and widespread use of mouse models to study concepts related to human health and disease, 44 we developed a complementary set of mouse Siglec-Fc soluble proteins for this study and used them to examine binding to the CHST overexpressing U937 cells (Figure 2k, Figure S2). We find that mouse Siglecs conserved between mouse and human (Siglec-1, CD22, and Siglec-15) 45 showed similar patterns as their human counterparts.…”

Section: Chst-dependent Binding Of Siglecs To U937 Cellsmentioning

confidence: 99%

Carbohydrate sulfation as a mechanism for fine-tuning Siglec ligands

Jung

Enterina

Bui

et al. 2021

Preprint

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The immunomodulatory family of Siglecs recognize sialic acid-containing glycans as self, which is exploited in cancer for immune-evasion. The biochemical nature of Siglec ligands remains incompletely understood with emerging evidence suggesting the importance of carbohydrate sulfation. Here, we investigate how specific sulfate modifications affect Siglec ligands by overexpressing eight carbohydrate sulfotransferases (CHSTs) in five cell lines. Overexpression of three CHSTs (CHST1, CHST2, or CHST4) significantly enhances the binding of numerous Siglecs. Unexpectedly, two other CHSTs (Gal3ST2 and Gal3ST3) diminish Siglec binding, suggesting a new mode to modulate Siglec ligands via sulfation. Results are cell type dependent, indicating that the context in which sulfated glycans are presented is important. Moreover, pharmacological blockade of N- and O-glycan maturation reveals a cell type-specific pattern of importance for either class of glycan. Production of a highly homogenous CD33 (Siglec-3) fragment enabled a mass spectrometry-based binding assay to determine 10-fold and 3-fold enhanced affinity for Neu5Acα2-3(6-O-sulfo)Galβ1-4GlcNAc and Neu5Acα2-3Galβ1-4(6-O-sulfo)GlcNAc, respectively, over Neu5Acα2-3Galβ1-4GlcNAc. CD33 showed significant additivity in affinity (36-fold) for the disulfated ligand, Neu5Acα2-3(6-O-sulfo)Galβ1-4(6-O-sulfo)GlcNAc. Moreover, overexpression of both CHST1 and CHST2 in cells greatly enhanced the binding of several Siglecs, including CD33. Finally, we reveal that CHST1 is upregulated in numerous cancers, correlating with poorer survival rates and sodium chlorate sensitivity for the binding of Siglecs to cancer cell lines. These results provide new insights into carbohydrate sulfation as a modification that is a general mechanism for tuning Siglec ligands on cells, including in cancer.

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“…In addition, the sialylation pattern and density also change in certain diseases, namely in cancer, which can be also attended with the alteration in the expression of some siglecs. In this context, the study of siglecs and their interactions with sialylated ligands becomes an attractive strategy to develop therapies targeting siglecs ( Angata et al, 2015 ; Duan and Paulson, 2020 ; Läubli et al, 2020 ; Läubli and Varki, 2020 ).…”

Section: Sialic Acid—siglec Interactionsmentioning

confidence: 99%

Molecular Recognition Insights of Sialic Acid Glycans by Distinct Receptors Unveiled by NMR and Molecular Modeling

Soares

Grosso

Ereño‐Orbea

et al. 2021

Front. Mol. Biosci.

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All cells are decorated with a highly dense and complex structure of glycan chains, which are mostly attached to proteins and lipids. In this context, sialic acids are a family of nine-carbon acidic monosaccharides typically found at the terminal position of glycan chains, modulating several physiological and pathological processes. Sialic acids have many structural and modulatory roles due to their negative charge and hydrophilicity. In addition, the recognition of sialic acid glycans by mammalian cell lectins, such as siglecs, has been described as an important immunological checkpoint. Furthermore, sialic acid glycans also play a pivotal role in host–pathogen interactions. Various pathogen receptors exposed on the surface of viruses and bacteria are responsible for the binding to sialic acid sugars located on the surface of host cells, becoming a critical point of contact in the infection process. Understanding the molecular mechanism of sialic acid glycans recognition by sialic acid-binding proteins, present on the surface of pathogens or human cells, is essential to realize the biological mechanism of these events and paves the way for the rational development of strategies to modulate sialic acid-protein interactions in diseases. In this perspective, nuclear magnetic resonance (NMR) spectroscopy, assisted with molecular modeling protocols, is a versatile and powerful technique to investigate the structural and dynamic aspects of glycoconjugates and their interactions in solution at the atomic level. NMR provides the corresponding ligand and protein epitopes, essential for designing and developing potential glycan-based therapies. In this review, we critically discuss the current state of knowledge about the structural features behind the molecular recognition of sialic acid glycans by different receptors, naturally present on human cells or pathogens, disclosed by NMR spectroscopy and molecular modeling protocols.

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Tools to study and target the Siglec–sialic acid axis in cancer

Abstract: Heinz L€ aubli and Kunio Kawanishi have contributed equally.

Cited by 37 publications

References 156 publications

The Paired Siglecs in Brain Tumours Therapy: The Immunomodulatory Effect of Dexamethasone and Temozolomide in Human Glioma In Vitro Model

The Paired Siglecs in Brain Tumours Therapy: The Immunomodulatory Effect of Dexamethasone and Temozolomide in Human Glioma In Vitro Model

Carbohydrate sulfation as a mechanism for fine-tuning Siglec ligands

Molecular Recognition Insights of Sialic Acid Glycans by Distinct Receptors Unveiled by NMR and Molecular Modeling

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