ST6GalNAc-I regulates tumor cell sialylation via NECTIN2/MUC5AC-Mediated Immunosuppression and Angiogenesis in Non-Small Cell Lung Cancer

Authors

Muthamil Iniyan Appadurai, University of Nebraska Medical CenterFollow
Sanjib Chaudhary, University of Nebraska Medical CenterFollow
Ashu Shah, University of Nebraska Medical CenterFollow
Gopalakrishnan Natarajan, University of Nebraska Medical CenterFollow
Zahraa W. Alsafwani, University of Nebraska Medical CenterFollow
Parvez Khan, University of Nebraska Medical CenterFollow
Dhananjay D. Shinde, University of Nebraska Medical CenterFollow
Subodh M. Lele, University of Nebraska Medical CenterFollow
Lynette M. Smith, University of Nebraska Medical CenterFollow
Mohd W. Nasser, University of Nebraska Medical CenterFollow
Surinder K. Batra, University of Nebraska Medical CenterFollow
Apar Kishor Ganti, University of Nebraska Medical CenterFollow
Imayavaramban Lakshmanan, University of Nebraska Medical CenterFollow

Document Type

Article

Journal Title

The Journal of Clinical Investigation

Publication Date

5-15-2025

Volume

135

Abstract

Glycosylation controls immune evasion, tumor progression, and metastasis. However, how tumor cell sialylation regulates immune evasion remains poorly characterized. ST6GalNAc-I, a sialyltransferase that conjugates sialic acid to the glycans in glycoproteins, was overexpressed in an aggressive-type KPA (KrasG12D/+ Trp53R172H/+ Ad-Cre) lung adenocarcinoma (LUAD) model and patient samples. Proteomic and biochemical analysis indicated that ST6GalNAc-I mediated NECTIN2 sialylation in LUAD cells. ST6GalNAc-I-deficient tumor cells cocultured with T cells were more susceptible to T cell-mediated tumor cell killing, indicating a key role for NECTIN2 in T cell dysfunction. Mice injected with St6galnac-I-knockdown syngeneic cells showed reduced lung tumor incidence and Nectin2/Tigit-associated immunosuppression. ST6GalNAc-I-deficient cells exhibited reduced P-DMEA metabolite levels, while administration of P-DMEA promoted LUAD cell proliferation via MUC5AC. MUC5AC interacted and colocalized with PRRC1 in the Golgi, suggesting a potential role for PRRC1 in MUC5AC glycosylation. Mice injected with ST6GalNAc-I/MUC5AC-deficient cells (human LUAD) exhibited reduced lung tumor incidence, angiogenesis, and liver metastases. Mechanistically, ST6GalNAc-I/MUC5AC regulates VCAN-V1, a key factor in tumor matrix remodeling during angiogenesis and metastasis. These findings demonstrate that ST6GalNAc-I-mediated sialylation of NECTIN2/MUC5AC is critical for immune evasion and tumor angiogenesis. Targeting this pathway may prevent LUAD development and/or metastasis.

MeSH Headings

Animals, Humans, Lung Neoplasms, Mice, Nectins, Carcinoma, Non-Small-Cell Lung, Sialyltransferases, Neovascularization, Pathologic, Neoplasm Proteins, Cell Line, Tumor, Angiogenesis

ISSN

1558-8238

DOI Link

10.1172/JCI186863

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

Appadurai, Muthamil Iniyan; Chaudhary, Sanjib; Shah, Ashu; Natarajan, Gopalakrishnan; Alsafwani, Zahraa W.; Khan, Parvez; Shinde, Dhananjay D.; Lele, Subodh M.; Smith, Lynette M.; Nasser, Mohd W.; Batra, Surinder K.; Ganti, Apar Kishor; and Lakshmanan, Imayavaramban, "ST6GalNAc-I regulates tumor cell sialylation via NECTIN2/MUC5AC-Mediated Immunosuppression and Angiogenesis in Non-Small Cell Lung Cancer" (2025). Journal Articles: Biochemistry & Molecular Biology. 173.
https://digitalcommons.unmc.edu/com_bio_articles/173