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Integrated Systems Analysis of the Murine and Human Pancreatic Cancer Glycomes Reveals a Tumor-Promoting Role for ST6GAL1

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Molecular and Cellular Proteomics 2021年 20卷 100160-100160页

作者： Kurz, Emma Chen, Shuhui Vucic, Emily Baptiste, Gillian Loomis, Cynthia Agrawal, Praveen Hajdu, Cristina Bar-Sagi, Dafna Mahal, Lara K. Department of Cell Biology NYU Grossman School of Medicine New York NY United States Department of Chemistry Biomedical Research Institute New York University New York NY United States Department of Biochemistry and Molecular Pharmacology NYU Grossman School of Medicine New York NY United States Department of Pathology NYU Grossman School of Medicine New York NY United States Office of Science and Research NYU Grossman School of Medicine New York NY United States

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States. Glycans, such as carbohydrate antigen 19-9, are biomarkers of PDAC and are emerging as important modulators of cancer phenotypes. Herein, we used a systems-based approach integrating glycomic analysis of the well-established KC mouse, which models early events in transformation, and analysis of samples from human pancreatic cancer patients to identify glycans with potential roles in cancer formation. We observed both common and distinct patterns of glycosylation in pancreatic cancer across species. Common alterations included increased levels of α-2,3-sialic acid and α-2,6-sialic acid, bisecting GlcNAc and poly-N-acetyllactosamine. However, core fucose, which was increased in human PDAC, was not seen in the mouse, indicating that not all human glycomic changes are observed in the KC mouse model. In silico analysis of bulk and single-cell sequencing data identified ST6 beta-galactoside alpha-2,6-sialyltransferase 1, which underlies α-2,6-sialic acid, as overexpressed in human PDAC, concordant with histological data showing higher levels of this enzyme at the earliest stages. To test whether ST6 beta-galactoside alpha-2,6-sialyltransferase 1 promotes pancreatic cancer, we created a novel mouse in which a pancreas-specific genetic deletion of this enzyme overlays the KC mouse model. The analysis of our new model showed delayed cancer formation and a significant reduction in fibrosis. Our results highlight the importance of a strategic systems approach to identifying glycans whose functions can be modeled in mouse, a crucial step in the development of therapeutics targeting glycosylation in pancreatic cancer. © 2021 American Society for Biochemistry and Molecular Biology Inc.. All rights reserved.

关键词： lectin microarray glycosylation ST6GAL1 pancreatic cancer lectin array

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Cross Validation of Liquid Chromatography-Mass Spectrometry and lectin array for Monitoring Glycosylation in Fed-Batch Glycoprotein Production

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MOLECULAR BIOTECHNOLOGY 2012年第3期51卷 272-282页

作者： Hayes, Catherine A. Doohan, Roisin Kirkley, David Leister, Kirk Harhen, Brendan Savage, Angela V. Karlsson, Niclas G. Bristol Myers Squibb Co Syracuse NY USA Natl Univ Ireland Sch Chem Galway Ireland

Glycosylation analysis of recombinant glycoproteins is of importance for the biopharmaceutical industry and the production of glycoprotein pharmaceuticals. A commercially available lectin array technology was evaluated for its ability to present a reproducible fingerprint of a recombinant CTLY4-IgG fusion glycoprotein expressed in large scale CHO-cell fermentation. The glycosylation prediction from the array was compared to traditional negative mode capillary LC-MS of released oligosaccharides. It was shown that both methods provide data that allow samples to be distinguished by their glycosylation pattern. This included information about sialylation, the presence of reducing terminal galactose beta 1-, terminal N-acetylglucosamine beta 1-, and antennary distribution. With both methods it was found that a general trend of increased sialylation was associated with an increase of the antenna and reduced amount of terminal galactose beta 1-, while N-acetylglucosamine beta 1- was less affected. LC-MS, but not the lectin array, provided valuable information about the sialic acid isoforms present, including N-acetylneuraminic acid, N-glycolylneuraminic acid and their O-acetylated versions. Detected small amounts of high-mannose structures by LC-MS correlated with the detection of the same epitope by the lectin array.

关键词： Glycosylation High mannose Acetylation N-linked oligosaccharides lectin array Mass spectrometry

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Alterations in the glycome after HDAC inhibition impact oncogenic potential in epigenetically plastic SW13 cells

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BMC CANCER 2019年第1期19卷 79-79页

作者： Montgomery, McKale R. Hull, Elizabeth E. Oklahoma State Univ Coll Human Sci Stillwater OK 74078 USA Midwestern Univ Coll Grad Studies Biomed Sci Program Glendale AZ 85308 USA

BackgroundDefects in the type and degree of cellular glycosylation impact oncogenesis on multiple levels. Although the type of glycosylation is determined by protein sequence encoded by the genome, the extent and modifications of glycosylation depends on the activity of biosynthetic enzymes and recent data suggests that the glycome is also subject to epigenetic regulation. This study focuses on the ability of HDAC inhibition to alter glycosylation and to lead to pro-oncogenic alterations in the glycome as assessed by metastatic potential and *** plastic SW13 adrenocortical carcinoma cells were treated with FK228, an HDAC inhibitor with high affinity for HDAC1 and, to a lesser extent, HDAC2. In comparing HDAC inhibitor treated and control cells, differential expression of glycome-related genes were assessed by microarray. Differential glycosylation was then assessed by lectin binding arrays and the ability of cellular proteins to bind to glycans was assessed by glycan binding arrays. Differential sensitivity to paclitaxel, proliferation, and MMP activity were also *** with FK228 alters expression of enzymes in the biosynthetic pathways for a large number of glycome related genes including enzymes in all major glycosylation pathways and several glycan binding proteins. 84% of these differentially expressed glycome-related genes are linked to cancer, some as prognostic markers and others contributing basic oncogenic functions such as metastasis or chemoresistance. Glycan binding proteins also appear to be differentially expressed as protein extracts from treated and untreated cells show differential binding to glycan arrays. The impact of differential mRNA expression of glycosylation enzymes was documented by differential lectin binding. However, the assessment of changes in the glycome is complicated by the fact that detection of differential glycosylation through lectin binding is dependent on the methods used t

关键词： Glycome expression HDAC inhibition Chemoresistance Gene expression profiling Glycan array lectin array Epigenetics

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Vitronectin (Vn) glycosylation patterned by lectin affinity assaysA potent glycoproteomic tool to discriminate plasma Vn from cancer ascites Vn

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JOURNAL OF MOLECULAR RECOGNITION 2018年第5期31卷 e2690-e2690页

作者： Benachour, H. Leroy-Dudal, J. Agniel, R. Wilson, J. Briand, M. Carreiras, F. Gallet, O. Univ Cergy Pontoise Inst Mat I MAT FD4122ERRMECe EA1391 Equipe Rech Relat Matrice Extracellulaire Cellule Neuville Sur Oise France RayBiotech Inc Norcross GA USA Normandie Univ UNICAEN BioTICLA Axis Biol & Innovat Therapeut Ovarian Ca INSERM ANTICIPE Interdisciplinary Res Unit Canc P Caen France UNICANCER Comprehens Canc Ctr Francois Baclesse CRB Biol Resources Ctr OvaRessources Caen France

Changes in glycosylation have been associated with human cancer, but their complexity poses an analytical challenge. Ovarian cancer is a major cause of death in women because of an often late diagnosis. At least one-third of patients presents ascites fluid at diagnosis, and almost all have ascites at recurrence. Vitronectin (Vn) is a multifunctional glycoprotein that is suggested to be implicated in ovarian cancer metastasis and is found within ascites. The present study evaluated the potential of using lectin affinity for characterizing the glycosylation pattern of Vn. Human Vn was purified from 1 sample of ovarian cancer ascites or a pool of plasma samples. Consistent findings were observed with both dot blot and lectin array assays. Based on a panel of 40 lectins, the lectin array revealed discriminant patterns of lectin binding to Vn glycans. Interestingly, almost all the highlighted interactions were found to be higher with Vn from ascites relative to the plasma counterpart. Also, the lectin array was able to discriminate profiles of lectin interactions (ConA, SNA-I, PHA-E, PHA-L) between Vn samples that were not evident using dot blot, indicating its high sensitivity. The model of ConA binding during thermal unfolding of Vn confirmed the higher accessibility of mannosylated glycans in Vn from ascites as monitored by turbidimetry. Thus, this study demonstrated the usefulness of lectins and the lectin array as a glycoproteomic tool for high throughput and sensitive analysis of glycosylation patterns. Our data provide novel insights concerning Vn glycosylation patterns in clinical specimens, paving the way for further investigations regarding their functional impact and clinical interest.

关键词： extracellular matrix glycoproteomics glycosylation human plasma lectin affinity lectin array ovarian cancer ascites vitronectin

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Cancer stem cell marker glycosylation: Nature, function and significance

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GLYCOCONJUGATE JOURNAL 2017年第4期34卷 441-452页

作者： Mallard, Brody W. Tiralongo, Joe Griffith Univ Inst Glyc Gold Coast Campus Gold Coast Qld 4222 Australia

Glycans are essential for the maintenance of normal biological function, with alterations in glycan expression being a hallmark of cancer. Cancer stem cells (CSCs) are a subset of cells within a tumour capable of self-renewal, cellular differentiation and resistances to conventional therapies. As is the case with stem cells, marker proteins present on the cell surface are frequently used to identify and enrich CSCs, with the expression of these markers statistical correlating with the likelihood of cancer recurrence and overall patient survival. As such CSC markers are of high clinical relevance. The majority of markers currently used to identify CSC populations are glycoproteins, and although the diverse biological roles for many of these markers are known, the nature and function of the glycan moiety on these glycoproteins remains to be fully elucidated. This mini-review summarises our current knowledge regarding the types and extent of CSC marker glycosylation, and the various roles that these glycans play in CSC biology, including in mediating cell adhesion, metastasis, evading apoptosis, tear shear resistance, tumour growth, maintaining pluripotency, self-renewal, trafficking, maintaining stability, maintaining enzymatic activity and aiding epithelial mesenchymal transitioning. Given that CSCs markers have multiple diverse biological functions, and are potentially of significant diagnostic and therapeutic benefit the search for new markers that are uniquely expressed on CSCs is vital to selectively target/identify this subset of cancer cells. As such we have also outlined how high-throughput lectin microarrays can be used to successfully profile the glycosylation status of CSC and to identify glyco-markers unique to CSCs.

关键词： Cancer Cancer stem cells Cancer stem cell markers CD44 CD133 Glycosylation Glycoproteins lectin array

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A Systems Biology Approach Identifies FUT8 as a Driver of Melanoma Metastasis

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CANCER CELL 2017年第6期31卷 804-+页

作者： Agrawal, Praveen Fontanals-Cirera, Barbara Sokolova, Elena Jacob, Samson Vaiana, Christopher A. Argibay, Diana Davalos, Veronica McDermott, Meagan Nayak, Shruti Darvishian, Farbod Castillo, Mireia Ueberheide, Beatrix Osman, Iman Fenyo, David Mahal, Lara K. Hernando, Eva NYU Sch Med Dept Pathol New York NY 10016 USA NYU Sch Med Perlmutter Canc Ctr Interdisciplinary Melanoma Cooperat Grp New York NY 10016 USA NYU Dept Chem Inst Biomed Chem New York NY 10003 USA NYU Sch Med Dept Biochem & Mol Pharmacol New York NY 10016 USA NYU Sch Med Inst Syst Genet New York NY 10016 USA NYU Sch Med Dept Dermatol New York NY 10016 USA Mt Sinai Hlth Syst Icahn Sch Med Mt Sinai Dept Pathol New York NY 10029 USA

Association of aberrant glycosylation with melanoma progression is based mainly on analyses of cell lines. Here we present a systems-based study of glycomic changes and corresponding enzymes associated with melanoma metastasis in patient samples. Upregulation of core fucosylation (FUT8) and downregulation of alpha-1,2 fucosylation (FUT1, FUT2) were identified as features of metastatic melanoma. Using both in vitro and in vivo studies, we demonstrate FUT8 is a driver of melanoma metastasis which, when silenced, suppresses invasion and tumor dissemination. Glycoprotein targets of FUT8 were enriched in cell migration proteins including the adhesion molecule L1CAM. Core fucosylation impacted L1CAM cleavage and the ability of L1CAM to support melanoma invasion. FUT8 and its targets represent therapeutic targets in melanoma metastasis.

关键词： primary melanoma metastatic melanoma glycosylation lectin microarray lectin array core fucosylation metastasis glycomics FUT8 L1CAM

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lectin microarray technology identifies specific lectins related to lymph node metastasis of advanced gastric cancer

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GASTRIC CANCER 2016年第2期19卷 531-542页

作者： Yamashita, Keishi Kuno, Atsushi Matsuda, Atsushi Ikehata, Yuzuru Katada, Natsuya Hirabayashi, Jun Narimatsu, Hisashi Watanabe, Masahiko Kitasato Univ Sch Med Dept Surg Minami Ku Asamizodai 2-1-1 Sagamihara Kanagawa 2520380 Japan Natl Inst Adv Ind Sci & Technol Res Ctr Med Glycosci AIST Tsukuba Cent 2 Tsukuba Ibaraki 3058568 Japan

Although various molecular profiling technologies have the potential to predict specific tumor phenotypes, the comprehensive profiling of lectin-bound glycans in human cancer tissues has not yet been achieved. We examined 242 advanced gastric cancer (AGC) patients without or with lymph node metastasis-N0 (n = 62) or N+ (n = 180)-by lectin microarray, and identified the specific lectins highly associated with AGC phenotypes. In seven gastric cancer cell lines, in contrast to expressed-in-cancer lectins, not-expressed-in-cancer (NEC) lectins were tentatively designated by lectin microarray. Binding signals of the specific lectins were robustly reduced in AGC patients with N+ status as compared with those with N0 status. The receiver operating characteristic curve determined the optimal cutoff value to differentiate N0 status from N+ status, and subsequent profiling of NEC lectins identified Vicia villosa agglutinin (VVA) association with the significant other lectins involved in lymph node metastasis. VVA reaction was clearly found on cancer cells, suggesting that it may result from carcinoma-stroma interaction in primary AGC, because VVA is an NEC lectin. Most intriguingly, VVA reaction was remarkably attenuated in the tumor cells of the metastatic lymph nodes, even if it was recognized in primary AGC. In AGC, histological type was strongly associated with soybean agglutinin and Bauhinia purpurea lectin, whereas p53 mutation was the best correlated with Griffonia simplicifolia lectin II. lectin microarrays can be used to very accurately quantify the reaction of glycans with tumor tissues, and such profiles may represent the specific phenotypes, including N+ status, histological type, or p53 mutation of AGC.

关键词： lectin array Gastric cancer Lymph node metastasis Vicia villosa agglutinin Prognosis

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Characterization of the N-glycans of female Angiostrongylus cantonensis worms

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EXPERIMENTAL PARASITOLOGY 2016年 166卷 137-143页

作者： Verissimo, Carolina M. Morassutti, Alessandra L. von Itzstein, Mark Sutov, Grigorij Hartley-Tassell, Lauren McAtamney, Sarah Dell, Anne Haslam, Stuart M. Graeff-Teixeira, Carlos Pontificia Univ Catolica Rio Grande Sul PUCRS Inst Pesquisas Biomed Lab Parasitol Mol BR-90060900 Porto Alegre RS Brazil Pontificia Univ Catolica Rio Grande Sul PUCRS Fac Biociencias Lab Biol Parasitaria BR-90060900 Porto Alegre RS Brazil Griffith Univ Inst Glyc Southport Qld 4222 Australia Univ London Imperial Coll Sci Technol & Med Fac Nat Sci Dept Life Sci London SW7 2AZ England

Glycoconjugates play a crucial role in the host-parasite relationships of helminthic infections, including angiostrongyliasis. It has previously been shown that the antigenicity of proteins from female Angiostrongylus cantonensis worms may depend on their associated glycan moieties. Here, an N-glycan profile of A. cantonensis is reported. A total soluble extract (TE) was prepared from female A. cantonensis worms and was tested by western blot before and after glycan oxidation or N- and O-glycosidase treatment. The importance of N-glycans for the immunogenicity of A. cantonensis was demonstrated when deglycosylation of the TE with PNGase F completely abrogated IgG recognition. The TE was also fractionated using various lectin columns [Ulex europaeus (UEA), concanavalin A (Con A), Arachis hypogaea (PNA), Triticum vulgaris (WGA) and Lycopersicon esculentum (LEA)I, and then each fraction was digested with PNGase F. Released N-glycans were analyzed with matrix-assisted laser desorption ionization (MALDI)-time-offlight (TOF)-mass spectrometry (MS) and MALDI-TOF/TOF-MS/MS. Complex-type, high mannose, and truncated glycan structures were identified in all five fractions. Sequential MALDI-TOF-TOF analysis of the major MS peaks identified complex-type structures, with a alpha 1-6 fucosylated core and truncated antennas. Glycoproteins in the TE were labeled with BodipyAF558-SE dye for a lectin microarray analysis. Fluorescent images were analyzed with ProScanarray imaging software followed by statistical analysis. A total of 29 lectins showed positive binding to the TE. Of these, Bandeiraea simplicifolia (BS-I), PNA, and Wisteria floribunda (WFA), which recognize galactose (Gal) and N-acetylgalactosamine (GaINAc), exhibited high affinity binding. Taken together, our findings demonstrate that female A. cantonensis worms have characteristic helminth N-glycans. (C) 2016 Elsevier Inc. All rights reserved.

关键词： Angiostrongylus cantonensis Glycans lectin array Mass spectrometry

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Carbohydrates analysis in herbal glycomics

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TRAC-TRENDS IN ANALYTICAL CHEMISTRY 2013年 52卷 155-169页

作者： Li, Shao-ping Wu, Ding-tao Lv, Guang-ping Zhao, Jing State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical Sciences University of Macau Macao SAR China

Herbs serve primary healthcare needs and some herbs are widely used as functional foods. Analysis of carbohydrates is essential to understand their structure-function relationships in food science and herbal medicine. However, accurately defining chemical structures of glycans is a challenge due to their chemical heterogeneity and diversity. We review and discuss carbohydrates as new functional ingredients in herbs and functional foods, and their analysis, a novel aspect in quality control and herbal glycomics. (c) 2013 Elsevier Ltd. All rights reserved.

关键词： Atomic force microscopy (AFM) Carbohydrate Chromatography Functional food Herbal glycomics Herbal ingredient lectin array Mass spectrometry (MS) Multiple-angle laser-light scattering (MALLS) Quality control (QC)

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Glycoproteomic Discovery of Serological Biomarker Candidates for HCV/HBV Infection-Associated Liver Fibrosis and Hepatocellular Carcinoma

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JOURNAL OF PROTEOME RESEARCH 2013年第6期12卷 2630-2640页

作者： Kaji, Hiroyuki Ocho, Makoto Togayachi, Akira Kuno, Atsushi Sogabe, Maki Ohkura, Takashi Nozaki, Hirofumi Angata, Takashi Chiba, Yasunori Ozaki, Hidenori Hirabayashi, Jun Tanaka, Yasuhito Mizokami, Masashi Ikehara, Yuzuru Narimatsu, Hisashi Natl Inst Adv Ind Sci & Technol Res Ctr Med Glycosci Tsukuba Ibaraki Japan Nagoya City Univ Dept Virol Grad Sch Med Sci Nagoya Aichi Japan Nagoya City Univ Grad Sch Med Sci Liver Unit Nagoya Aichi Japan

We previously proposed a high-throughput strategy to discover serological biomarker candidates of cancer. This strategy focuses on a series of candidate glycoproteins that are specifically expressed in the original tissues (cells) of the target cancer and that carry glycan structures associated with carcinogenesis [Narimatsu, H., et al. FEBS J. 2010, 277(1), 95-105]. Here, we examined the effectiveness of our strategy in identifying biomarkers to assess progression of liver fibrosis and for the early detection of hepatocellular carcinoma (HCC). On the basis of the results of lectin array analyses in culture media of hepatoma cell lines, we captured glycopeptides carrying AAL-ligands (fucosylated glycans) or DSA-ligands (branched glycans) from digests of culture media proteins and sera from HCC patients with a background of liver cirrhosis (LC). Glycoproteins were identified by the IGOT-LC-MS method. In all, 21 candidates were selected from 744 AAL-bound glycoproteins for further verification according to (i) their abundance in serum, (ii) their specific expression in liver, and (iii) the availability of antibodies to the glycoproteins. All selected candidates showed enhancement of AAL-reactivity in sera of HCC patients compared with that of healthy volunteers (HV). These results indicate that our glycoproteomic strategy is effective for identifying multiple glyco-biomarker candidates in a high-throughput manner.

关键词： glycoprotein glycan alteration hepatocellular carcinoma liver fibrosis biomarker lectin array glycoproteomics

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