Tumor-associated-fibrosis and active collagen-CD44 axis characterize a poor-prognosis subtype of gastric cancer and contribute to tumor immunosuppression
Abstract Background Tumor-associated fibrosis modifies the tumor microenvironment (TME), hinders the infiltration and activity of cytotoxic immune cells, and is a critical pathological process leading to the ineffectiveness of tumor immunotherapy in gastric cancer (GC). However, the specific mechani...
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2025-01-01
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| Online Access: | https://doi.org/10.1186/s12967-025-06070-9 |
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| author | Yingqi Yang Haohan Sun Hongkai Yu Luyao Wang Chang Gao Haokun Mei Xiaomeng Jiang Minghui Ji |
| author_facet | Yingqi Yang Haohan Sun Hongkai Yu Luyao Wang Chang Gao Haokun Mei Xiaomeng Jiang Minghui Ji |
| author_sort | Yingqi Yang |
| collection | DOAJ |
| description | Abstract Background Tumor-associated fibrosis modifies the tumor microenvironment (TME), hinders the infiltration and activity of cytotoxic immune cells, and is a critical pathological process leading to the ineffectiveness of tumor immunotherapy in gastric cancer (GC). However, the specific mechanisms and interventions are yet to be fully explored. Methods Our study included 375 gastric cancer samples from TCGA, 1 single-cell RNA sequencing (scRNA-seq) dataset comprising of 15 gastric cancer samples from GEO, 19 cohorts of immunotherapy and 2 GWAS datasets. Consensus clustering identified a gastric cancer subtype characterized primarily by fibrosis, and various methods such as pseudotime analysis, CellChat analysis and Colocalization analysis were used to explore its mechanisms. Results A subtype of gastric cancer was identified with poor prognosis, characterized by higher malignancy, drug resistance, and poor immune infiltration, associated with elevated expression of genes related with Extracellular matrix (ECM). Single-cell transcriptome analysis showed active Collagen-CD44 signaling axis between cancer-associated fibroblasts (CAFs) and immune cells in gastric cancer, with ECM-related genes upregulated during tumor progression. The expression of CD44 was significantly elevated in the subtype, associated with poor prognosis and tumor immune suppression in gastric cancer, potentially involved in the recruitment of immunosuppressive cells such as M2 macrophages and regulatory T cells (Tregs) and the upregulation of multiple immune checkpoints including PD-1/PD-L1. Conclusion Our study identified a new subtype of gastric cancer, revealing that fibrosis is a critical mechanism driving immune suppression in gastric cancer and emphasizing the central role of the Collagen-CD44 signaling axis. The Collagen-CD44 signaling axis has the potential to serve as a novel therapeutic target for gastric cancer by enhancing immune cell-mediated tumor suppression. By combining it with immune checkpoint inhibitors (ICIs), it may improve the efficacy of immunotherapy for gastric cancer and offer new hope for treatment. |
| format | Article |
| id | doaj-art-d1712d905ba84d6b980ed722be5ed578 |
| institution | Kabale University |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-d1712d905ba84d6b980ed722be5ed5782025-02-02T12:40:32ZengBMCJournal of Translational Medicine1479-58762025-01-0123111610.1186/s12967-025-06070-9Tumor-associated-fibrosis and active collagen-CD44 axis characterize a poor-prognosis subtype of gastric cancer and contribute to tumor immunosuppressionYingqi Yang0Haohan Sun1Hongkai Yu2Luyao Wang3Chang Gao4Haokun Mei5Xiaomeng Jiang6Minghui Ji7The Second School of Clinical Medicine, Nanjing Medical UniversityThe Second School of Clinical Medicine, Nanjing Medical UniversityThe Second School of Clinical Medicine, Nanjing Medical UniversityThe Second School of Clinical Medicine, Nanjing Medical UniversityThe Second School of Clinical Medicine, Nanjing Medical UniversityThe Fourth School of Clinical Medicine, Nanjing Medical UniversityDepartment of Gastroenterology, Sir Run Run Hospital, Nanjing Medical UniversitySchool of Nursing, Nanjing Medical UniversityAbstract Background Tumor-associated fibrosis modifies the tumor microenvironment (TME), hinders the infiltration and activity of cytotoxic immune cells, and is a critical pathological process leading to the ineffectiveness of tumor immunotherapy in gastric cancer (GC). However, the specific mechanisms and interventions are yet to be fully explored. Methods Our study included 375 gastric cancer samples from TCGA, 1 single-cell RNA sequencing (scRNA-seq) dataset comprising of 15 gastric cancer samples from GEO, 19 cohorts of immunotherapy and 2 GWAS datasets. Consensus clustering identified a gastric cancer subtype characterized primarily by fibrosis, and various methods such as pseudotime analysis, CellChat analysis and Colocalization analysis were used to explore its mechanisms. Results A subtype of gastric cancer was identified with poor prognosis, characterized by higher malignancy, drug resistance, and poor immune infiltration, associated with elevated expression of genes related with Extracellular matrix (ECM). Single-cell transcriptome analysis showed active Collagen-CD44 signaling axis between cancer-associated fibroblasts (CAFs) and immune cells in gastric cancer, with ECM-related genes upregulated during tumor progression. The expression of CD44 was significantly elevated in the subtype, associated with poor prognosis and tumor immune suppression in gastric cancer, potentially involved in the recruitment of immunosuppressive cells such as M2 macrophages and regulatory T cells (Tregs) and the upregulation of multiple immune checkpoints including PD-1/PD-L1. Conclusion Our study identified a new subtype of gastric cancer, revealing that fibrosis is a critical mechanism driving immune suppression in gastric cancer and emphasizing the central role of the Collagen-CD44 signaling axis. The Collagen-CD44 signaling axis has the potential to serve as a novel therapeutic target for gastric cancer by enhancing immune cell-mediated tumor suppression. By combining it with immune checkpoint inhibitors (ICIs), it may improve the efficacy of immunotherapy for gastric cancer and offer new hope for treatment.https://doi.org/10.1186/s12967-025-06070-9FibrosisGastric cancerImmunosuppression |
| spellingShingle | Yingqi Yang Haohan Sun Hongkai Yu Luyao Wang Chang Gao Haokun Mei Xiaomeng Jiang Minghui Ji Tumor-associated-fibrosis and active collagen-CD44 axis characterize a poor-prognosis subtype of gastric cancer and contribute to tumor immunosuppression Journal of Translational Medicine Fibrosis Gastric cancer Immunosuppression |
| title | Tumor-associated-fibrosis and active collagen-CD44 axis characterize a poor-prognosis subtype of gastric cancer and contribute to tumor immunosuppression |
| title_full | Tumor-associated-fibrosis and active collagen-CD44 axis characterize a poor-prognosis subtype of gastric cancer and contribute to tumor immunosuppression |
| title_fullStr | Tumor-associated-fibrosis and active collagen-CD44 axis characterize a poor-prognosis subtype of gastric cancer and contribute to tumor immunosuppression |
| title_full_unstemmed | Tumor-associated-fibrosis and active collagen-CD44 axis characterize a poor-prognosis subtype of gastric cancer and contribute to tumor immunosuppression |
| title_short | Tumor-associated-fibrosis and active collagen-CD44 axis characterize a poor-prognosis subtype of gastric cancer and contribute to tumor immunosuppression |
| title_sort | tumor associated fibrosis and active collagen cd44 axis characterize a poor prognosis subtype of gastric cancer and contribute to tumor immunosuppression |
| topic | Fibrosis Gastric cancer Immunosuppression |
| url | https://doi.org/10.1186/s12967-025-06070-9 |
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