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Deciphering IFN signaling in gastric cancer: A single-cell and bulk transcriptomic integration reveals CXCR4 as a key
Jintian Song1, Feihua Wu2, Yi Wang3
1Department of Gastrointestinal Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350014, Fujian Province, China.
Background:
Gastric cancer (GC), a prevalent solid tumor, features a complex tumor microenvironment (TME) that influences immunotherapy responses. Leveraging single-cell RNA sequencing (scRNA-seq) and bulk transcriptomics, we dissect the interplay between interferon (IFN) signaling and GC TME to identify actionable targets.
Methods:
We analyzed bulk and scRNA-seq datasets. Gene Set Variation Analysis evaluated IFN pathway activity. The Scissor (single-cell identification of subpopulations with bulk sample phenotype correlation) algorithm and weighted gene co-expression network analysis identified survival-associated, IFN-correlated cellular subpopulations. Cell-cell communication within TME was mapped. A multi-gene prognostic signature was constructed and validated. qRT-PCR and Western blot detected marker gene expression. Flow cytometry assessed the proportion of macrophage polarization. CCK-8, Transwell, and scratch assays evaluated cell proliferation and migration.
Results:
High IFN activity correlated with improved patient survival. scRNA-seq revealed macrophages and dendritic cells as primary IFN-activity hubs. Macrophages linked to poor prognosis (Scissor+) exhibited the strongest IFN-γ-driven communication with tumor cells. We established a robust IFN-related prognostic model and pinpointed CXCR4 as a key adverse prognostic biomarker tightly coupled to IFN signaling. Low CXCR4 with high IFN activity defined a favorable prognostic profile. In cell experiments, CXCR4 deficiency in macrophages activated the IFN signaling pathway. Its overexpression reversed the inhibitory effect of IFN-γ treatment on malignant phenotype of AGS cells.
Conclusions:
This study elucidates IFN signaling network within the GC TME at single-cell resolution. We provide a prognostic model and identify CXCR4 as a promising therapeutic target, shedding mechanistic insights for refining immunotherapy strategies in GC.
Insights
High interferon (IFN) activity in gastric cancer (GC) correlates with better survival. Targeting CXCR4 shows promise for improving immunotherapy in GC patients.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Gastric cancer (GC) has a complex tumor microenvironment (TME) affecting immunotherapy.
- Understanding interferon (IFN) signaling within the GC TME is crucial for treatment.
Purpose of the Study:
- To dissect the interplay between IFN signaling and the GC TME.
- To identify actionable therapeutic targets for GC immunotherapy.
Main Methods:
- Analysis of bulk and single-cell RNA sequencing (scRNA-seq) datasets.
- Utilized Scissor algorithm and weighted gene co-expression network analysis.
- Investigated cell-cell communication and constructed a prognostic model.
Main Results:
- High IFN activity positively correlated with patient survival.
- Macrophages and dendritic cells are key IFN activity hubs in GC TME.
- CXCR4 identified as an adverse prognostic biomarker linked to IFN signaling.
Conclusions:
- Elucidated the IFN signaling network in GC TME at single-cell resolution.
- Developed a prognostic model and identified CXCR4 as a therapeutic target.
- Provided mechanistic insights for enhancing GC immunotherapy.
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