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GI cancer
Original research
NNMT enriches for AQP5+ cancer stem cells to drive malignant progression in early gastric cardia adenocarcinoma
  1. Zhangding Wang1,
  2. Qiang Wang2,
  3. Chen Chen3,
  4. Xiaoya Zhao3,
  5. Honggang Wang4,
  6. Lei Xu1,
  7. Yao Fu5,
  8. Guang Huang6,
  9. Mengmeng Li3,
  10. Jiawen Xu3,
  11. Qianyi Zhang3,
  12. Bo Wang7,
  13. Guifang Xu1,
  14. Lei Wang1,
  15. Xiaoping Zou1,8,
  16. Shouyu Wang7,9
  1. 1Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People’s Republic of China
  2. 2Department of Hepatobiliary Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, People’s Republic of China
  3. 3Medical School of Nanjing University, Nanjing, Jiangsu Province, People’s Republic of China
  4. 4Department of Gastroenterology, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu Province, People’s Republic of China
  5. 5Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People’s Republic of China
  6. 6Center for Global Health, Key Lab of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
  7. 7Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People’s Republic of China
  8. 8Department of Gastroenterology, Affiliated Taikang Xianlin Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, People’s Republic of China
  9. 9Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu Province, People’s Republic of China
  1. Correspondence to Professor Shouyu Wang, Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People's Republic of China; sywang{at}nju.edu.cn; Professor Xiaoping Zou, Department of Gastroenterology, Affiliated Taikang Xianlin Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, People’s Republic of China; 13770771661{at}163.com; Professor Lei Wang, Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People’s Republic of China; leiwang9631{at}nju.edu.cn; Professor Guifang Xu, Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People’s Republic of China; 13852293376{at}163.com

Abstract

Objective Early gastric cardia adenocarcinoma (EGCA) is a highly heterogeneous cancer, and the understanding of its classification and malignant progression is limited. This study explored the cellular and molecular heterogeneity in EGCA using single-cell RNA sequencing (scRNA-seq).

Design scRNA-seq was conducted on 95 551 cells from endoscopic biopsies of low-grade intraepithelial neoplasia, well/moderately/poorly differentiated EGCA and their paired adjacent nonmalignant biopsy samples. Large-scale clinical samples and functional experiments were employed.

Results Integrative analysis of epithelial cells revealed that chief cells, parietal cells and enteroendocrine cells were rarely detected in the malignant epithelial subpopulation, whereas gland and pit mucous cells and AQP5+ stem cells were predominant during malignant progression. Pseudotime and functional enrichment analyses showed that the WNT and NF-κB signalling pathways were activated during the transition. Cluster analysis of heterogeneous malignant cells revealed that NNMT-mediated nicotinamide metabolism was enriched in gastric mucin phenotype cell population, which was associated with tumour initiation and inflammation-induced angiogenesis. Furthermore, the expression level of NNMT was gradually increased during the malignant progression and associated with poor prognosis in cardia adenocarcinoma. Mechanistically, NNMT catalysed the conversion of nicotinamide to 1-methyl nicotinamide via depleting S-adenosyl methionine, which led to a reduction in H3K27 trimethylation (H3K27me3) and then activated the WNT signalling pathway to maintain the stemness of AQP5+ stem cells during EGCA malignant progression.

Conclusion Our study extends the understanding of the heterogeneity of EGCA and identifies a functional NNMT+/AQP5+ population that may drive malignant progression in EGCA and could be used for early diagnosis and therapy.

  • NNMT
  • AQP5
  • cancer stem cells
  • tumorigenesis
  • early cardia carcinoma

Data availability statement

Data are available on reasonable request.

http://dx.doi.org/10.1136/gutjnl-2022-328408

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    Data availability statement

    Data are available on reasonable request.

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    Footnotes

    • ZW, QW, CC, XZ and HW are joint first authors.

    • ZW, QW, CC, XZ and HW contributed equally.

    • Contributors All authors are responsible for the overall content as the guarantors. ZW analysed the scRNA-seq data; ZW, QW, CC and XZ performed the experiments; LX, GX, LW, XPZ and HW provided the biopsies; ML, QZ, BW and HW evaluated the IHC of TMA; FY was responsible for the pathological staining interpretation; GH was responsible for the metabolite measurement; ZW and SW wrote the paper; SW designed the project. All the authors read and approved the final manuscript.

    • Funding This work was supported in part by the National Natural Science Foundation of China (82273157, 82102984, 82073114, 81903085, 81773383); and the natural science foundation of Jiangsu Province (BK20200132); and the Nanjing special foundation for health science and technology development (distinguished young programme, JQX22005, JQX21005). The work was also supported by Research Fund of Anhui Institute of translational medicine (2022zhyx-C21) and Outstanding Youth Scientific Research Projects in colleges and universities of Anhui Province (2022AH030115) and Postgraduate Research & Practice Innovation Programme of Jiangsu Province (KYCX22_0175).

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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