Impaired glycosylation of gastric mucins drives gastric tumorigenesis and serves as a novel therapeutic target

Junya Arai; Yoku Hayakawa; Hiroaki Tateno; Keita Murakami; Takeru Hayashi; Masahiro Hata; Yuki Matsushita; Hiroto Kinoshita; Sohei Abe; Ken Kurokawa; Yukiko Oya; Mayo Tsuboi; Sozaburo Ihara; Ryota Niikura; Nobumi Suzuki; Yusuke Iwata; Toshiro Shiokawa; Chihiro Shiomi; Chie Uekura; Keisuke Yamamoto; Hiroaki Fujiwara; Satoshi Kawamura; Hayato Nakagawa; Seiya Mizuno; Takashi Kudo; Satoru Takahashi; Tetsuo Ushiku; Yoshihiro Hirata; Chifumi Fujii; Jun Nakayama; Shinsuke Shibata; Susan Woods; Daniel L Worthley; Masanori Hatakeyama; Timothy C Wang; Mitsuhiro Fujishiro

doi:10.1053/j.gastro.2024.03.037

Impaired glycosylation of gastric mucins drives gastric tumorigenesis and serves as a novel therapeutic target

Gastroenterology. 2024 Apr 5:S0016-5085(24)00363-9. doi: 10.1053/j.gastro.2024.03.037. Online ahead of print.

Authors

Junya Arai¹, Yoku Hayakawa², Hiroaki Tateno³, Keita Murakami⁴, Takeru Hayashi⁵, Masahiro Hata⁴, Yuki Matsushita⁴, Hiroto Kinoshita⁴, Sohei Abe⁴, Ken Kurokawa⁴, Yukiko Oya⁴, Mayo Tsuboi⁴, Sozaburo Ihara⁴, Ryota Niikura⁴, Nobumi Suzuki⁴, Yusuke Iwata⁴, Toshiro Shiokawa⁴, Chihiro Shiomi⁴, Chie Uekura⁴, Keisuke Yamamoto⁴, Hiroaki Fujiwara¹, Satoshi Kawamura⁶, Hayato Nakagawa⁶, Seiya Mizuno⁷, Takashi Kudo⁸, Satoru Takahashi⁸, Tetsuo Ushiku⁹, Yoshihiro Hirata⁴, Chifumi Fujii¹⁰, Jun Nakayama¹¹, Shinsuke Shibata¹², Susan Woods¹³, Daniel L Worthley¹⁴, Masanori Hatakeyama⁵, Timothy C Wang¹⁵, Mitsuhiro Fujishiro⁴

Affiliations

¹ Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; Division of Gastroenterology, The Institute of Medical Science, Asahi Life Foundation, Tokyo, Japan.
² Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. Electronic address: yhayakawa-tky@umin.ac.jp.
³ Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan. Electronic address: h-tateno@aist.go.jp.
⁴ Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
⁵ Division of Microbiology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
⁶ Department of Gastroenterology, Graduate School of Medicine, University of Mie, Tokyo, Japan.
⁷ Laboratory Animal Resource Center in Transborder Medical Research Center, and Department of Laboratory Animal Science, Institute of Medicine, University of Tsukuba, Ibaraki, Japan.
⁸ Laboratory Animal Resource Center in Transborder Medical Research Center, and Department of Anatomy and Embryology, Institute of Medicine, University of Tsukuba, Ibaraki, Japan.
⁹ Department of Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
¹⁰ Department of Molecular Pathology, Shinshu University School of Medicine, Matsumoto, Japan; Department of Biotechnology, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto, Japan.
¹¹ Department of Molecular Pathology, Shinshu University School of Medicine, Matsumoto, Japan.
¹² Division of Microscopic Anatomy, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
¹³ Precision Cancer Medicine Theme, SAHMRI, Adelaide, South Australia, Australia; Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia.
¹⁴ Colonoscopy Clinic, Brisbane, Queensland, Australia.
¹⁵ Division of Digestive and Liver disease, Department of Medicine, Columbia University, New York, New York.

PMID: 38583723
DOI: 10.1053/j.gastro.2024.03.037

Abstract

Background: Gastric cancer is often accompanied by a loss of MUC6, but its pathogenic role in gastric carcinogenesis remains unclear.

Method: Muc6 knockout (Muc6-/-) mice and Muc6-dsRED mice were newly generated. Tff1Cre, Golph3-/-, R26-Golgi-mCherry, Hes1^flox/flox, Cosmc^flox/flox, A4gnt-/- mice were also used. Histology, DNAs and RNAs, proteins, and sugar chains were analyzed by whole exon DNA sequence, RNA sequence, immunohistochemistry, lectin-binding assays, and LC-MS analysis. Gastric organoids and cell lines were used for in vitro assays and xenograft experiments.

Result: Deletion of Muc6 in mice spontaneously causes pan-gastritis and invasive gastric cancers. Muc6-deficient tumor growth was dependent on MAPK activation, mediated by Golgi stress-induced upregulation of GOLPH3. Glycomic profiling revealed aberrant expression of mannose-rich N-linked glycans in gastric tumors, detected with Banana lectin in association with lack of MUC6 expression. We identified a precursor of clusterin as a binding partner of mannose glycans. MAPK activation, Golgi stress responses, aberrant mannose expression are found in a separate Cosmc- and A4gnt-deficient mouse models which lack normal O-glycosylation. Banana lectin-drug conjugates proved an effective treatment for mannose-rich murine and human gastric cancer.

Conclusion: We propose that Golgi stress responses and aberrant glycans are important drivers of, and promising new therapeutic targets for gastric cancer.

Keywords: GOLPH3; Golgi stress; MAPK pathway; Muc6; gastric cancer.