ArticleClinical and experimental medicine2025
Notch pathway defines an aggressive and immune-suppressive phenotype associated with checkpoint inhibitor resistance in pan-gastrointestinal adenocarcinomas.
Article in Clinical and experimental medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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3 citing papers in PubMed.
- Targeting the Notch signaling pathway in digestive system cancers: from bench to bedside.Cancer cell international · 2026Review
- Multidimensional immune ecological subtyping identifies RUNX1 as a prognostic factor in uveal melanoma.Discover oncology · 2026Article
- Emerging roles of Notch signaling in the tumor microenvironment of digestive system cancers.Frontiers in molecular biosciences · 2026Review
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12 authors.
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Abstract
The Notch pathway regulates the homeostasis and tumorigenesis of gastrointestinal epithelium. Given its roles in cancer stem cell capacity and cancer immunity, we hypothesized that Notch activation can predict poor prognosis and resistance to immune checkpoint inhibitors (ICIs) in gastrointestinal adenocarcinoma (GIAC). The mRNA expression and genomic alterations of Notch pathway were characterized in esophagus (ESAD), stomach (STAD), colon (COAD), or rectum (READ) adenocarcinomas from The Cancer Genome Atlas (TCGA) dataset. The prognostic model (mRNA-score) was constructed using the TCGA dataset (the training set) and was validated in 3 independent sets (GSE19417 [ESAD], GSE84437 [STAD], and GSE40967 [COAD]). The associations of the mRNA-score with drug sensitivity, immune cell infiltration, and immunotherapy efficacy were, respectively, analyzed using the Genomics of Drug Sensitivity in Cancer (GDSC) database, the TCGA dataset, and multiple clinical cohorts including GSE165252, PRJEB25780, IMvigor210, and CheckMate-009/010/025. Notch pathway genes exhibited conserved genomic/transcriptomic features across four GIAC subtypes. Three pan-GIAC clusters were determined by unsupervised clustering, and the cluster with higher expression of the Notch pathway genes had shorter overall survival (OS), immunosuppressive microenvironment, and higher scores of the signatures concerning angiogenesis, cell cycle, PI3K-AKT-mTOR, TGF-β, glycolysis, etc. A prognostic algorithm (mRNA-score) was constructed, which was correlated with poor OS in the training set (TCGA, P < 0.001) and three validation sets (GSE19417, P = 0.025; GSE84437, P = 0.001, GSE40967, P = 0.007). A high mRNA-score was linked with more "resting"/ "anti-inflammatory" rather than "activated"/ "pro-inflammatory" tumor-infiltrating immune cells and ICI resistance in GIACs (GSE165252, P = 0.047; PRJEB25780, P = 0.047) and other solid tumors such as urothelial carcinoma and clear cell renal cell carcinoma. Our findings demonstrate the utility of the Notch pathway in predicting prognosis and ICI resistance. Further studies are warranted to explore the efficacy of Notch inhibitors as immunotherapeutic adjuvants to overcome ICI resistance.
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