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Updated: Jan 10, 2026
Author Spotlight: Unveiling Transmembrane Protein Family-Related Markers in Gastric Cancer and Implications for Targeted Therapies
Published on: September 15, 2023
Multi-omics analysis reveals the heterogeneity and interactions among stromal and tumor cells in gastric cancer
Chenyu Yang1, Yue Jin1, Xiaoyi Zhao1
1Departments of Gastroenterology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Jiangsu 214023, PR China; Jiangsu Branch of the National Clinical Research Center for Digestive Diseases, Wuxi, Jiangsu 214023, China.
Objective:
This study aims to investigate the heterogeneity of cancer-associated fibroblasts (CAFs) and smooth muscle cells (SMCs) and their interactions with malignant epithelium in gastric cancer (GC), with the goal of identifying potential therapeutic targets.
Methods:
We performed a multi-omics analysis integrating single-cell RNA sequencing and spatial transcriptomics, complemented by trajectory inference, regulon activity mapping, ligand-receptor interaction modeling, and survival association in external cohorts.
Results:
Two malignant epithelial programs emerged-Tumor Cell 1 (TC 1) (wound-healing/proliferative) and Tumor Cell 1 (TC 2) (highly cycling/metabolic). In TCGA-STAD (The Cancer Genome Atlas - Stomach Adenocarcinoma), high TC 1 scores associated with worse overall survival (P < 0.01), whereas TC 2 showed a nonsignificant trend. The stroma comprised nine populations; tumors were enriched for RGS5⁺ SMCs and FAP⁺ fibroblasts, with depletion of homeostatic PI16⁺ fibroblasts. Pseudotime traced a PI16⁺→CCL11⁺→PDGFRA⁺→FAP⁺ continuum featuring late NF-κB/STAT activation and extracellular matrix (ECM)-remodeling; SMCs rewired from contractile MYH11⁺ to angiocrine RGS5⁺ states. Ligand-receptor analysis indicated asymmetric tumor-stroma crosstalk: TC 1 preferentially engaged vaso-regulatory/EGFR-immune signaling to activate CAFs and SMCs, while TC 2 amplified PDGF/MDK growth-factor circuits; stromal feedback via WNT/NRG/HGF/TGF-β reinforced malignant programs. Spatial maps confirmed EPCAM-high tumor nests encased by COL1A2/FAP⁺ fibroblastic shells interwoven with ACTA2/RGS5⁺ strands.
Conclusion:
This study highlights the critical role of CAFs and SMCs heterogeneity and their interactions within the GC TME (Tumor microenvironment). Targeting stromal pathways such as PDGF, TGF-β, and NF-κB signaling, immunomodulating CAFs, and disrupting SMC-derived vascular niches may improve therapeutic responses. Further experimental validation of ligand-receptor pairs and spatial determinants is warranted.
