2. Academic Validation
  3. NNMT enriches for AQP5+ cancer stem cells to drive malignant progression in early gastric cardia adenocarcinoma

NNMT enriches for AQP5+ cancer stem cells to drive malignant progression in early gastric cardia adenocarcinoma

  • Gut. 2023 Mar 28;gutjnl-2022-328408. doi: 10.1136/gutjnl-2022-328408.
Zhangding Wang # 1,  Qiang Wang # 2,  Chen Chen # 3,  Xiaoya Zhao # 3,  Honggang Wang # 4,  Lei Xu 1,  Yao Fu 5,  Guang Huang 6,  Mengmeng Li 3,  Jiawen Xu 3,  Qianyi Zhang 3,  Bo Wang 7,  Guifang Xu 8,  Lei Wang 8,  Xiaoping Zou 8 9,  Shouyu Wang 10 11
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People's Republic of China.
  • 2 Department of Hepatobiliary Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, People's Republic of China.
  • 3 Medical School of Nanjing University, Nanjing, Jiangsu Province, People's Republic of China.
  • 4 Department of Gastroenterology, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu Province, People's Republic of China.
  • 5 Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People's Republic of China.
  • 6 Center 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 Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People's Republic of China.
  • 8 Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People's Republic of China [email protected] [email protected] [email protected] [email protected].
  • 9 Department of Gastroenterology, Affiliated Taikang Xianlin Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, People's Republic of China.
  • 10 Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People's Republic of China [email protected] [email protected] [email protected] [email protected].
  • 11 Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu Province, People's Republic of China.
  • # Contributed equally.
PMID: 36977555 DOI: 10.1136/gutjnl-2022-328408
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.

Keywords

AQP5; NNMT; cancer stem cells; early cardia carcinoma; tumorigenesis.

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