Multi-omics mapping of TIMP1-associated stromal–myeloid remodeling in autoimmune gastritis and gastric cancer

Abstract

Autoimmune gastritis (AIG) is a chronic immune-mediated atrophic disease that can induce cancer-related epithelial remodeling, although its association with gastric adenocarcinoma depends on histological and clinical modifiers. Gastric cancer (GC) progression is shaped by the tumor microenvironment (TME), including cancer-associated fibroblasts (CAFs), myeloid cells, and extracellular matrix (ECM) remodeling. Whether AIG-related mucosal remodeling shares stromal programs with GC-associated stromal–myeloid niches remains unclear. We integrated one AIG bulk-transcriptomic cohort and three GC cohorts to identify shared differentially expressed genes (DEGs), followed by LASSO, random forest and protein–protein interaction (PPI) analyses. TIMP1 was evaluated using tissue transcriptomic cohorts, serum RT-qPCR, survival analysis, immune infiltration profiling, scRNA-seq, inferCNV-based epithelial classification, CellChat ligand–receptor inference and spatial transcriptomics. A total of 51 shared DEGs were identified between AIG and GC. TIMP1 was the only candidate supported by both machine-learning screening and PPI hub-gene analysis. TIMP1 was upregulated in GC tissues and serum and showed an exploratory tumor–normal ROC AUC of 0.941 in the TCGA_STAD cohort, while higher TIMP1 expression was associated with poorer overall survival. Functional analyses linked TIMP1-high GC to ECM organization, integrin binding, epithelial-mesenchymal transition (EMT), transforming growth factor-β signaling and immune infiltration. scRNA-seq of 160,812 GC cells localized TIMP1 mainly to CAF and myeloid compartments. In AIG, TIMP1-high fibroblasts displayed enhanced CAF-associated stromal and inflammatory transcriptional programs. CellChat and spatial transcriptomics further linked TIMP1-associated stromal and myeloid states to ECM-dominant communication and fibroblast-rich, myeloid-associated remodeling regions. TIMP1 may mark related stromal–myeloid remodeling states across AIG-associated mucosal remodeling and GC, providing a hypothesis-generating framework potentially relevant to inflammation-associated gastric tumorigenesis.