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Outline
To systematically characterize tumor microenvironmental features and spatial cellular interactomes associated with distinct transcriptional meta-program (MP) in gastric cancer, and explore their clinical implications.
We integrated 2 gastric cancer single-cell RNA sequencing (scRNA-seq) datasets to identify malignant cell-derived transcriptional MP. The prognostic value was validated in 3 independent bulk transcriptomic cohorts: The Cancer Genome Atlas (TCGA), GSE15459, and GSE66229. Using scRNA-seq, we dissected MP-specific shifts in microenvironmental cell composition and inferred dominant ligand-receptor interactions. Spatial transcriptomics confirmed the co-localization of implicated cell subsets and signaling pairs. Survival analyses were used to access the associations between key cellular signatures/interaction signatures and patient outcomes.
Four MP from MP1 to MP4 were identified in malignant cells. High expression of MP2 and MP4 significantly correlated with worse overall survival (P<0.05). In MP2-high tumors, SPP1⁺ macrophages were enriched and predicted to interact with T3 neutrophils via the SPP1-CD44 ligand-receptor pair, with spatial co-localization validated. Both SPP1⁺ macrophage signature (P=0.007) and SPP1-CD44 interaction signature (P=0.008) predicted adverse prognosis. In MP4-high tumors, myofibroblastic cancer-associated fibroblast (myCAF) were expanded and showed interaction with exhausted CD8⁺ T cells through the COL6A family-ITGB1 signaling axis, which was also spatially validated. The myCAF signature (P=0.001) and COL6A family-ITGB1 interaction signature (P<0.001) correlated with poorer survival.
MP2 and MP4 delineate 2 distinct immunosuppressive spatial niches in gastric cancer: SPP1⁺ macrophage-T3 neutrophil and myCAF-exhausted CD8⁺ T cell. These niches likely drive tumor progression via SPP1-CD44 and COL6A family-ITGB1 axes, respectively, providing potential targets for precision immunotherapy.
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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