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Single-cell profiling of gastric cardia adenocarcinoma reveals drivers of cancer stemness and therapeutic targets
  1. Patrick Tan1,2,3,
  2. Yunqiang Chu1
  1. 1 Cancer Science Institute of Singapore, National University of Singapore, Singapore
  2. 2 Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore
  3. 3 Genome Institute of Singapore, Agency for Science, Singapore
  1. Correspondence to Dr Patrick Tan, Duke-NUS Graduate Medical School, Singapore, Singapore; gmstanp{at}duke-nus.edu.sg

https://doi.org/10.1136/gutjnl-2023-329887

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    Gastric cancer (GC) is a major cause of worldwide cancer mortality, accounting for >7 00 000 deaths in 2020.1 The stomach comprises two main anatomical areas—the proximal stomach (cardia, fundus and corpus) and the distal stomach (antrum and pylorus) (figure 1). While most GCs occur distally, about 18% of GCs occur as proximal gastric cardia adenocarcinoma (GCA).1 Currently, little is known about molecular pathways driving GCA tumourigenesis. Previous studies2 have highlighted genetic, epigenetic and transcriptional similarities between GCA and oesophageal adenocarcinoma (OAC). Nowicki-Osuch et al 3 4 reported that GCA and OAC may both arise from normal gastric cardia cells via gastric intestinal metaplasia and Barret’s oesophageal intestinal metaplasia, respectively.

    Figure 1

    Discovery of nicotinamide N-methyltransferase/aquaporin 5 (NNMT+/AQP5+) cell populations in gastric cardia adenocarcinoma (GCA). A single-cell atlas of GCA was established, from which malignant cells were classified into gastric-phenotype and intestinal-phenotype subpopulations. The gastric-phenotype subpopulation exhibited high NNMT expression in AQP5+ stem cells. In NNMT+/AQP5+ cells, NNMT regulates epigenetic alterations to activate Wnt signalling, stemness, and tumourigenesis. The NAPRT-mediated NAD synthesis pathway is termed the Preiss-Handler pathway. see Wang et al 10 for details. NAAD, nicotinic acid adenine dinucleotide; NAMN, nicotinic acid mononucleotide; NAMPT, nicotinamide phosphoribosyltransferase; NAPRT, nicotinate phosphoribosyltransferase; SAH, S-adenosyl homocysteine; SAM, S-adenosyl-L-methionine.

    Cancer stem cells (CSCs) play important roles in many cancer traits, including tumourigenesis, recurrence, metastasis and drug resistance. In GC, several molecules have been reported as CSC biomarkers. Using mouse models, Barker et al 5 reported that LGR5 (leucine-rich repeat-containing, …

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    Footnotes

    • Collaborators None.

    • Contributors PT and YC cowrite the commentary.

    • Funding YC is supported by a CSI Singapore PhD Graduate Scholarship. PT is supported by the Singapore Ministry of Health’s National Medical Research Council under Open Fund-Large Collaborative Grant ('OF-LCG') (MOH-OFLCG18May-0003), MOH-000967 and core funding to Duke-NUS and GIS. Support was also provided by the Cancer Science Institute of Singapore, National University of Singapore, through the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative.

    • Competing interests None declared.

    • Provenance and peer review Commissioned; externally peer reviewed.

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