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Division of Glycobiologics

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INTRODUCTION-ABOUT THE LABORATORY:

The Division of Glycobiologics was started as a new laboratory in October 2016 in Graduate School of Medicine, Juntendo University.

Glycobiology is a unique and rapidly developing area within molecular and cellular biology, which is now the foundation of all disciplines of medical sciences. Even after the sequence of the entire human genome became available, human health and diseases are filled with mysteries to be deciphered. Disease processes are often unpredictable, and innovative pharmaceuticals and medical devices are required to provide better treatment and cure. Glycosciences present new avenues to tackle these demands.

Glycoproteins, glycolipids and proteoglycans are implicated in the fine tunings of biological processes and the pathophysiology of diseases ever since the discovery of their diverse structures, dynamic biosynthetic regulation, and heavy localization on cell surfaces and in the extracellular milieu. Their structural diversity and the genetic basis for their biosynthetic regulation are highly evolved in higher vertebrates, particularly in humans. It is now time to translate the accumulated knowledge and the available tools into new medical resources.

We are interested to evolve glycosciences and apply the outcomes to understand disease processes and develop new modalities useful in the diagnosis and therapy of diseases particularly in the area of cancer and immunological disorders. Our endeavors strengthened by our close collaboration with clinical departments and pathologists at Juntendo University have been highly productive as revealed by the list of publications and patent applications.

CONTACT:

Division of Glycobiologics,
Juntendo University Graduate School of Medicine
Hongo 2-1-1 (4th Floor-North of 7th Building)
Telephone: +81-3-3813-3111 (ext 2114); +81-3-5802-1876 (direct)

OUTLINE OF RESEARCH PROJECTS:

Our long term goal is to understand disease processes based on glycobiology focusing primarily on cancer and immunological disorders. We also envision discovery of new drugs and medical devises based on the novel understanding of disease processes by glycobiology.

Specific aims are:

  1. To understand the biological behavior of cancer cells with clinical emphasis, such as recurrence, metastasis, and resistance to drugs, by focusing on lectins (carbohydrate recognition molecules), and mucins (carbohydrate displaying molecules).
    • We found that mucin 21 (MUC21) suppresses apoptosis in a glycoform-dependent manner.
    • We discovered carbohydrate structures unique to a subpopulation of triple-negative breast cancer cells, and elucidated the underlining mechanisms.
  2. To establish diagnostic and therapeutic applications for MUC1 and MUC21 with different sugar chains at unique positions.
    • We showed that a MUC1 DNA vaccine was effective in the prevention of inflammation-driven carcinogenesis in human MUC1 transgenic mice.
    • We developed antibodies that recognize combinations of a sugar chain and a specific amino acid sequence within the MUC1 tandem repeats, and are pursuing their application in diagnosis and therapy.
    • We established monoclonal antibodies specific for unique glycoforms of human MUC21 and mouse MUC21.
  3. To develop and produce antibodies that recognize combinations of sugar chains and backbone peptides and explore their possible uses as diagnostic and therapeutic agents.
    • We were successful in developing an anti-HER2 monoclonal antibody without potential cardiotoxicity based on the glycoforms.
  4. To clarify the importance of subsets of dendritic cells and macrophages expressing the C-type lectin MGL/CD301 in immune and inflammatory disorders, and to develop new therapeutic methods through the understanding of their functions.
    • Using a mouse model, we showed that MGL/CD301 recognizes sugar chains in the commensal microbiome and suppresses inflammation during the pathogenesis of inflammatory bowel disease.
    • By analyzing clinical specimens from atopic dermatitis and psoriasis patients, we found that MGL/CD301-positive subsets of macrophages and dendritic cells accumulate in affected skin lesions. We further aim to elucidate the important functions of MGL/CD301 in the pathogenesis in the hope of developing ways to control these diseases.

MEMBERS

Tatsuro Irimura
Ph.D., Affiliated Professor, Emeritus Professor of the University of Tokyo
Kaori Denda-Nagai
Ph.D., Project Assistant Professor, primary appointment with the Department of Medical Education
Haruhiko Fujihira
Ph.D., Visiting Assistant Professor, primary appointment with RIKEN
Miki Noji
Research Scientist
Katrin Ishii-Schrade
Ph.D., Research Assistant
Tomoko Shiina
Research Assistant
Kiyoko Jarnes
Administrative Assistant

PUBLICATIONS (2013-2023):

2023

  1. Murwanti R, Denda-Nagai K, Sugiura D, Mogushi K, Gendler SJ, Irimura T. Prevention of inflammation-driven colon carcinogenesis in human MUC1 transgenic mice by vaccination with MUC1 DNA and dendritic cells. Cancers, 15 (6):1920, 2023. PMID: 36980805, doi: 10.3390/cancers15061920.
  2. Manome-Zenke Y, Denda-Nagai K, Murakami R, Noji M, Tsuneda N, Ishii-Schrade K, Kanomata N, Arai S, Irimura T, Ikeda S. Possible involvement of antigen presenting cells expressing the macrophage galactose-type C type lectin in inflammatory skin diseases. J Invest Dermatol, published online, 2023. PMID: 36963610, doi: 10.1016/j.jid.2023.03.1654.
  3. Semba R, Horimoto Y, Sakata-Matsuzawa M, Ishizuka Y, Denda-Nagai K, Fujihira H, Noji M, Onagi H, Ichida M, Miura H, Watanabe J, Saito M, Saito T, Arakawa A, Irimura T. Possible correlation of apical localization of MUC1 glycoprotein with luminal A-like status of breast cancer. Sci Rep, 13(1):5281, 2023 .PMID: 37002293; doi: 10.1038/s41598-023-32579-4.

2022

  1. Tian Y, Denda-Nagai K, Tsukui T, Ishii-Schrade K, Okada K, Nishizono Y, Matsuzaki K, Hafley M, Bresalier RS, Irimura T. Mucin 21 confers resistance to apoptosis in an O-glycosylation-dependent manner. Cell Death Discov, 8(1) 194, 2022. PMID: 35410995, doi: 10.1038/s41420-022-01006-4.
  2. Nishida J, Shichino S, Tsukui T, Hoshino M, Okada T, Okada K, Yi Y, Toraya-Brown S, Mochizuki M, Koizumi R, Ishii-Schrade K, Denda-Nagai K, Irimura T. Unique Glycoform-Dependent Monoclonal Antibodies for Mouse Mucin 21. int J Mol Sci, 2022;23(12). PMID: 35743163; doi: 10.3390/ijms23126718.
  3. Shi J, Kanoya R, Tani Y, Ishikawa S, Maeda R, Suzuki S, Kawanami F, Miyagawa N, Takahashi K, Oku T, Yamamoto A, Fukuzawa K, Nakajima M, Irimura T, Higashi N. Sulfated hyaluronan binds to heparanase and blocks Its enzymatic and cellular actions in carcinoma cells. Int J Mol Sci, 23(99): 5055, 2022. PMID: 35563446, doi: 10.3390/ijms23095055.
  4. Kokubu R, Ohno S, Kuratani H, Takahashi Y, Manabe N, Shimizu H, Chiba Y, Denda-Nagai K, Tsuiji M, Irimura T, Yamaguchi Y. O-Glycan-dependent interaction between MUC1 Glycopeptide and MY.1E12 antibody by NMR, molecular dynamics and docking simulations. Int J Mol Sci, 23(14): 7855, 2022. PMID: 35887202, doi: 10.3390/ijms23147855.
  5. Hlaing MT, Horimoto Y, Denda-Nagai K, Fujihira H, Noji M, Kaji H, Tomioka A, Ishizuka Y, Saeki H, Arakawa A, Saito M, Irimura T. Tamoxifen-resistant breast cancer cells exhibit reactivity with Wisteria floribunda agglutinin. Plos One 17(8): e0273513, 2022. PMID: 36006984, doi: 10.1371/journal.pone.0273513.

2021

  1. Sakata-Matsuzawa M, Denda-Nagai K, Fujihira H, Noji M, Ishii-Schrade K, Matsuda A, Kuno A, Okazaki M, Nakai K, Horimoto Y, Saito M, Irimura T. Glycans unique to the relapse-prone subset within triple-negative breast cancer as revealed by lectin array-based analysis of surgical specimens. Plos One, 16(5): e0250747, 2021. PMID: 33974630, doi: 10.1371/journal.pone.0250747.
  2. Fujihira H, Takakura D, Matsuda A, Abe M, Miyazaki M, Nakagawa T, Kajino K, Denda-Nagai K, Noji M, Hino O, Irimura T. Bisecting-GlcNAc on Asn388 is characteristic to ERC/mesothelin expressed on epithelioid mesothelioma cells. J Biochem, 170(3): 317-326, 2021. PMID: 33792699, doi: 10.1093/jb/mvab044.
  3. Okazaki M, Mogushi K, Denda-Nagai K, Fujihira H, Noji M, Ishii-Schrade K, Sakata-Matsuzawa M, Nakai K, Horimoto Y, Saito M, Irimura T. Biological and clinicopathological implications of beta-3-N-acetylglucosaminyltransferase 8 in triple-negative breast cancer. Anticancer Res, 2021 Feb;41(2):845-858, 2021. PMID: 33517290, doi: 10.21873/anticanres.14837.
  4. Kurashina R, Denda-Nagai K, Saba K, Hisai T, Hara H, Irimura T. Intestinal lamina propria macrophages upregulate interleukin-10 mRNA in response to signals from commensal bacteria recognized by MGL1/CD301a. Glycobiology, 31(7):827-837, 2021. PMID: 33677516, doi: 10.1093/glycob/cwab015.
  5. Tamada Y, Nomura H, Aoki D, Irimura T. A possible inhibitory role of sialic acid on MUC1 in peritoneal dissemination of clear cell-type ovarian cancer cells. Molecules, 26: 5962, 2021. PMID: 34641504, doi: 10.3390/molecules26195962.

2020

  1. Higashi N, Irimura T, Nakajima M. Heparanase is involved in leukocyte migration. Adv Exp Med Biol, 1221:435-444, 2020. PMID: 32274720, doi: 10.1007/978-3-030-34521-1_16

2019

  1. Kanemaru K, Noguchi E, Tahara-Hanaoka S, Mizuno S, Tateno H, Denda-Nagai K, Irimura T, Matsuda H, Sugiyama F, Takahashi S, Shibuya K, Shibuya A. Clec10a regulates mite-induced dermatitis. Sci Immunol. 2019 Dec 6;4(42):eaax6908. doi: 10.1126/sciimmunol.aax6908.PMID: 31811054.
  2. Yoshimura Y, Denda-Nagai K, Takahashi Y, Nagashima I, Shimizu H, Kishimoto T, Noji M, Shichino S, Chiba Y, Irimura T. Products of chemoenzymatic synthesis representing MUC1 tandem repeat unit with T-, ST- or STn-antigen revealed distinct specificities of anti-MUC1 antibodies. Sci Rep. 2019 Nov 12;9(1):16641. doi: 10.1038/s41598-019-53052-1.
  3. Higashi N, Maeda R, Sesoko N, Isono M, Ishikawa S, Tani Y, Takahashi K, Oku T, Higashi K, Onishi S, Nakajima M, Irimura T. Chondroitin sulfate E blocks enzymatic action of heparanase and heparanase-induced cellular responses. Biochem Biophys Res Commun. 2019 Nov 26;520(1):152-158. doi: 10.1016/j.bbrc.2019.09.126.
  4. Yoshimoto T, Matsubara D, Soda M, Ueno T, Amano Y, Kihara A, Sakatani T, Nakano T, Shibano T, Endo S, Hagiwara K, Fukayama M, Denda-Nagai K, Irimura T, Mano H, Niki T. Mucin 21 is a key molecule involved in the incohesive growth pattern in lung adenocarcinoma. Cancer Sci. 2019 Sep;110(9):3006-3011. doi: 10.1111/cas.14129.
  5. Matsumura M, Okudela K, Nakashima Y, Mitsui H, Denda-Nagai K, Suzuki T, Arai H, Umeda S, Tateishi Y, Koike C, Kataoka T, Irimura T, Ohashi K. Specific expression of MUC21 in micropapillary elements of lung adenocarcinomas - Implications for the progression of EGFR-mutated lung adenocarcinomas. PLoS One. 2019 Apr 11;14(4):e0215237. doi: 10.1371/journal.pone.0215237.

2018

  1. Higashi N, Waki M, Sudo Y, Suzuki S, Oku T, Tsuiji M, Tsuji T, Miyagishi M, Takahashi K, Nakajima M, Irimura T. Incorporation, intracellular trafficking and processing of extracellular heparanase by mast cells: Involvement of syndecan-4-dependent pathway. Biochem Biophys Res Commun. 2018 Sep 18;503(4):3235-3241. doi: 10.1016/j.bbrc.2018.08.132.
  2. Fujihira H, Usami K, Matsuno K, Takeuchi H, Denda-Nagai K, Furukawa JI, Shinohara Y, Takada A, Kawaoka Y, Irimura T. A critical domain of Ebolavirus envelope glycoprotein determines glycoform and infectivity. Sci Rep. 2018 Apr 3;8(1):5495. doi: 10.1038/s41598-018-23357-8.
  3. Adachi H, Nakae K, Sakamoto S, Nosaka C, Atsumi S, Shibuya M, Higashi N, Nakajima M, Irimura T, Nishimura Y. Microbial metabolites and derivatives targeted at inflammation and bone diseases therapy: chemistry, biological activity and pharmacology. J Antibiot (Tokyo). 2017 Nov 1. doi: 10.1038/ja.2017.138.

2017

  1. Wu H, Tao A, Martin JD, Quader S, Liu X, Takahashi K, Hespel L, Miura Y, Hayakawa Y, Irimura T, Cabral H, Kataoka K.  Proteasome Inhibitor-Loaded Micelles Enhance Antitumor Activity Through Macrophage Reprogramming by NF-κB Inhibition.  J Pharm Sci. 2017 Apr 12. pii: S0022-3549(17)30217-4. doi: 10.1016/j.xphs.2017.03.031. [Epub ahead of print] PMID: 28412401
  2. Fujihira H, Masahara-Negishi Y, Tamura Y, Huang C, Harada Y, Wakana S, Takakura D, Kawasaki N, Taniguchi N, Kondoh G, Yamashita T, Funakoshi Y, Suzuki T. (2017)  Lethality of mice bearing a knockout of the Ngly1-gene is partially rescued by the additional deletion of the Engase gene.  PLOS Genet. 2017 Apr 20;13(4):e1006696. doi: 10.1371/journal.pgen.1006696, PMID: 28426790

2016

  1. Kimura Y, Nagai N, Tsunekawa N, Sato-Matsushita M, Yoshimoto T, Cua DJ, Iwakura Y, Yagita H, Okada F, Tahara H, Saiki I, Irimura T, Hayakawa Y.  IL-17A-producing CD30(+) Vδ1 T cells drive inflammation-induced cancer progression.  Cancer Sci. 2016 Sep;107(9):1206-14. doi: 10.1111/cas.13005. Epub 2016 Sep 1.  PMID: 27384869
  2. Sue M, Higashi N, Shida H, Kogane Y, Nishimura Y, Adachi H, Kolaczkowska E, Kepka M, Nakajima M, Irimura T.  An iminosugar-based heparanase inhibitor heparastatin (SF4) suppresses infiltration of neutrophils and monocytes into inflamed dorsal air pouches.Int Immunopharmacol. 2016 Jun;35:15-21. doi: 10.1016/j.intimp.2016.03.017. Epub 2016 Mar 22. PMID: 27015605
  3. Hayakawa Y, Kawada M, Nishikawa H, Ochiya T, Saya H, Seimiya H, Yao R, Hayashi M, Kai C, Matsuda A, Naoe T, Ohtsu A, Okazaki T, Saji H, Sata M, Sugimura H, Sugiyama Y, Toi M, Irimura T.  Report on the use of non-clinical studies in the regulatory evaluation of oncology drugs.  Cancer Sci. 2016 Feb;107(2):189-202. doi: 10.1111/cas.12857. Review.  PMID: 26919617
  4. Tsunekawa N, Higashi N, Kogane Y, Waki M, Shida H, Nishimura Y, Adachi H, Nakajima M, Irimura T.  Heparanase augments inflammatory chemokine production from colorectal carcinoma cell lines.  Biochem Biophys Res Commun. 2016 Jan 22;469(4):878-83. doi: 10.1016/j.bbrc.2015.12.074. Epub 2015 Dec 20.  PMID: 26713365

2015

  1. Xin X, Akasaka-Manya K, Manya H, Furukawa J, Kuwahara N, Okada K, Tsumoto H, Higashi N, Kato R, Shinohara Y, Irimura T, Endo T.  POMGNT1 Is Glycosylated by Mucin-Type O-Glycans.  Biol Pharm Bull. 2015;38(9):1389-94. doi: 10.1248/bpb.b15-00415.  PMID: 26328495
  2. Matsuda A, Kuno A, Nakagawa T, Ikehara Y, Irimura T, Yamamoto M, Nakanuma Y, Miyoshi E, Nakamori S, Nakanishi H, Viwatthanasittiphong C, Srivatanakul P, Miwa M, Shoda J, Narimatsu H.  Lectin Microarray-Based Sero-Biomarker Verification Targeting Aberrant O-Linked Glycosylation on Mucin 1.  Anal Chem. 2015 Jul 21;87(14):7274-81. doi: 10.1021/acs.analchem.5b01329. Epub 2015 Jul 7.  PMID: 26091356
  3. Takahashi K, Nagai N, Ogura K, Tsuneyama K, Saiki I, Irimura T, Hayakawa Y.  Mammary tissue microenvironment determines T cell-dependent breast cancer-associated inflammation.   Cancer Sci. 2015 Jul;106(7):867-74. doi: 10.1111/cas.12685. Epub 2015 May 29.  PMID: 25940224

2014

  1. Kee JY, Ito A, Hojo S, Hashimoto I, Igarashi Y, Tsuneyama K, Tsukada K, Irimura T, Shibahara N, Takasaki I, Inujima A, Nakayama T, Yoshie O, Sakurai H, Saiki I, Koizumi K.  CXCL16 suppresses liver metastasis of colorectal cancer by promoting TNF-α-induced apoptosis by tumor-associated macrophages.  BMC Cancer. 2014 Dec 15;14:949. doi: 10.1186/1471-2407-14-949.  PMID: 25495942
  2. Lou C, Takahashi K, Irimura T, Saiki I, Hayakawa Y.  Identification of Hirsutine as an anti-metastatic phytochemical by targeting NF-κB activation.  Int J Oncol. 2014 Nov;45(5):2085-91. doi: 10.3892/ijo.2014.2624. Epub 2014 Aug 27.  PMID: 25175557
  3. Miyahara N, Shoda J, Kawamoto T, Ishida H, Ueda T, Akimoto Y, Kawakami H, Irimura T.  Interaction of Muc4 and ErbB2 in a transgenic mouse model of gallbladder carcinoma: potential pathobiological implications.  Oncol Rep. 2014 Nov;32(5):1796-802. doi: 10.3892/or.2014.3443. Epub 2014 Aug 25.  PMID: 25174601
  4. Kim SJ, Wang YG, Lee HW, Kang HG, La SH, Choi IJ, Irimura T, Ro JY, Bresalier RS, Chun KH. Up-regulation of neogenin-1 increases cell proliferation and motility in gastric cancer. Oncotarget. 2014 May 30;5(10):3386-98.  PMID: 24930499
  5. Higashi N, Waki M, Sue M, Kogane Y, Shida H, Tsunekawa N, Hasan A, Sato T, Kitahara A, Kasaoka T, Hayakawa Y, Nakajima M, Irimura T.  Heparanase-mediated cleavage of macromolecular heparin accelerates release of granular components of mast cells from extracellular matrices.  Biochem J. 2014 Mar 1;458(2):291-9. doi: 10.1042/BJ20131463. PMID: 24344642
  6. Ng WC, Liong S, Tate MD, Irimura T, Denda-Nagai K, Brooks AG, Londrigan SL, Reading PC. The macrophage galactose-type lectin can function as an attachment and entry receptor for influenza virus.  J Virol. 2014 Feb;88(3):1659-72. doi: 10.1128/JVI.02014-13. Epub 2013 Nov 20.  PMID: 24257596
  7. Murakami R, Denda-Nagai K, Hashimoto S, Nagai S, Hattori M, Irimura T.  A unique dermal dendritic cell subset that skews the immune response toward Th2.  PLoS One. 2013 Sep 9;8(9):e73270. doi: 10.1371/journal.pone.0073270. eCollection 2013. Erratum in: PLoS One. 2014;9(3):e93236.  PMID: 24039898

2013

  1. Goudarzi H, Iizasa H, Furuhashi M, Nakazawa S, Nakane R, Liang S, Hida Y, Yanagihara K, Kubo T, Nakagawa K, Kobayashi M, Irimura T, Hamada J.  Enhancement of in vitro cell motility and invasiveness of human malignant pleural mesothelioma cells through the HIF-1α-MUC1 pathway.  Cancer Lett. 2013 Oct 1;339(1):82-92. doi: 10.1016/j.canlet.2013.07.020. Epub 2013 Jul 20.  PMID: 23879962
  2. Takahashi K, Takeda K, Saiki I, Irimura T, Hayakawa Y.  Functional roles of tumor necrosis factor-related apoptosis-inducing ligand-DR5 interaction in B16F10 cells by activating the nuclear factor-κB pathway to induce metastatic potential.  Cancer Sci. 2013 May;104(5):558-62. doi: 10.1111/cas.12112. Epub 2013 Feb 28. PMID: 23347256

PATENT LIST

  1. Irimura T, Fujihira H, Denda-Nagai K, Saito M, Horimoto Y, Sasaki R, Noji M, Suzuki K, Akatsuka J, Ono K, Nishida S, Matsuura K, and Shimizu T: Anti-HER2 antibody and pharmaceuticals containing this antibody. 2021-42891(Filed on March 16, 2021)
  2. Irimura T, Denda-Nagai K, Noji M, Chiba Y, Sato T, Shimizu H, and Angata K: Antibodies which recognize MUC1 with sialyl-GalNAc residues. 2023-011092 (Filed on January 27, 2023)
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