COL1A1-positive endothelial cells promote gastric cancer progression via the ANGPTL4-SDC4 axis driven by endothelial-to-mesenchymal transition

Abstract

Gastric cancer (GC) is an aggressive and heterogeneous disease with poor survival outcomes. The progression of GC involves complex, multi-step processes. Endothelial cells (ECs) play a crucial role in tumor angiogenesis, proliferation, invasion, and metastasis, particularly through the process of endothelial-to-mesenchymal transition (EndoMT). However, the specific role and mechanisms of EndoMT in gastric cancer remain unclear. Based on 6 GC single-cell RNA-sequencing (scRNA-seq) cohorts (samples = 97), we established an EndoMT-related gene signature, termed EdMTS. Leveraging this gene signature, ssGSEA was applied to calculate sample scores across multiple bulk RNA-seq datasets, which include information on immunotherapy, metastasis, GC progression, and survival. Moreover, we applied the Monocle2 method to calculate cell pseudotime and used CellChat to analyze interactions between malignant and EC cells. We verified the molecular mechanism by multiple immunofluorescence and cell function experiments. Findings In this study, we established a single-cell atlas of ECs in GC and identified a subpopulation of COL1A1⁺ ECs that play a critical role in tumor progression and metastasis. These COL1A1⁺ ECs were significantly associated with worse clinical outcomes in GC patients. Further analysis revealed that COL1A1⁺ ECs originated from lymphatic ECs and underwent EndoMT through the upregulation of CEBPB, driving tumor invasiveness. Moreover, COL1A1⁺ ECs interacted with malignant cells via ANGPTL4-SDC4 axis, enhancing invasion and migration. These findings provide a deeper understanding of the role of COL1A1⁺ ECs in GC progression and highlight potential therapeutic targets for disrupting the EndoMT process in these cells to provide a benefit for GC patients.