Most mammalian cells and their secreted products are covered with a dense coating of sugar chains. In recent years, the technologies for studying these oligosaccharide chains on glycoconjugates have advanced rapidly, allowing an exploration of their biological roles. There is now increasing evidence that they play many important roles in complex organisms, ranging from simple structural integrity to the mediation of cell-cell interaction, intra- and inter-cellular trafficking, and cell growth and differentiation. Work in this laboratory is driven by the hypothesis that the more specific biological role of oligosaccharides are likely to be mediated by unusual terminal structures or by modifications such as O- acetylation, phosphorylation and sulfation. Our overall goal is to explore the biosynthesis, regulation and function of such oligosaccharide structures in health and disease. In work supported by this grant, we have identified and partially characterized novel families of sulfated N-linked oligosaccharides that are enriched in pulmonary artery endothelial cells, as well as in lung tissue. These include multi-antennary complex-type oligosaccharides carrying sialic acids and O-Sulfate esters (SSOs) and N-linked molecules carrying glycosaminoglycan-like chains attached to complex-type oligosaccharides (NLGs). We have also developed a novel technique for tagging free oligosaccharides via their reducing terminus with biotinylated amino- pyridine (BAP). In the current project period, we will continue the structural analysis of these molecules and use structurally defined BAP- SSO adducts to search for specific receptors for these oligosaccharides, and to raise monoclonal antibodies directed against them. In the course of these studies, we have identified a novel class of sulfated glycosaminoglycans that are calcium-dependent high affinity ligands for the leucocyte adhesion molecule, L-selectin. These appear to be distinct from the NLGs and SSOs mentioned above, and from the previously described mucin-like sulfated ligands for L-selectin on the high-endothelial venules (HBV) of lymph nodes. In the current project period, we will carry out a detailed structural comparison of these sulfated ligands, and identify the minimal oligosaccharide structural requirements for the biologically relevant interactions. We will also study the biosynthesis of these molecules in isolated intact Golgi-enriched preparations, and create novel fluorescent biotinylated primers for their biosynthesis in intact cells. Altered glycosylation is an universal feature of cancer cells, generating tumor antigens and diagnostic markers, and apparently mediating some of their abnormal behavior. It is likely that metastatic tumor cells subvert the mechanisms that normally mediate the migration and invasion of blood cells into tissues. Since endothelial cells must play crucial roles in the metastatic process, our study of their sulfated oligosaccharides could have an important bearing on the design of therapeutic interventions in cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Pathobiochemistry Study Section (PBC)
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University of California San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
United States
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Läubli, Heinz; Varki, Ajit; Borsig, Lubor (2016) Antimetastatic Properties of Low Molecular Weight Heparin. J Clin Oncol 34:2560-1
Schwarz, Flavio; Fong, Jerry J; Varki, Ajit (2015) Human-specific evolutionary changes in the biology of siglecs. Adv Exp Med Biol 842:1-16
Samraj, Annie N; Pearce, Oliver M T; Läubli, Heinz et al. (2015) A red meat-derived glycan promotes inflammation and cancer progression. Proc Natl Acad Sci U S A 112:542-7
Varki, Nissi M; Varki, Ajit (2015) On the apparent rarity of epithelial cancers in captive chimpanzees. Philos Trans R Soc Lond B Biol Sci 370:
Samraj, Annie N; Läubli, Heinz; Varki, Nissi et al. (2014) Involvement of a non-human sialic Acid in human cancer. Front Oncol 4:33
Chang, Yung-Chi; Olson, Joshua; Beasley, Federico C et al. (2014) Group B Streptococcus engages an inhibitory Siglec through sialic acid mimicry to blunt innate immune and inflammatory responses in vivo. PLoS Pathog 10:e1003846
Pearce, Oliver Mt; Läubli, Heinz; Bui, Jack et al. (2014) Hormesis in cancer immunology: Does the quantity of an immune reactant matter? Oncoimmunology 3:e29312
Läubli, Heinz; Pearce, Oliver M T; Schwarz, Flavio et al. (2014) Engagement of myelomonocytic Siglecs by tumor-associated ligands modulates the innate immune response to cancer. Proc Natl Acad Sci U S A 111:14211-6
Deng, Lingquan; Song, Jeongmin; Gao, Xiang et al. (2014) Host adaptation of a bacterial toxin from the human pathogen Salmonella Typhi. Cell 159:1290-9
Pearce, Oliver M T; Läubli, Heinz; Verhagen, Andrea et al. (2014) Inverse hormesis of cancer growth mediated by narrow ranges of tumor-directed antibodies. Proc Natl Acad Sci U S A 111:5998-6003

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