Bulk Sequencing Combined With Single‐Cell Sequencing Identifies High Expression of VCAN in Fibroblasts Promoting the Progression of High‐Stemness Gastric Adenocarcinoma Cells

Gastric cancer ranks as the fifth most prevalent malignancy and the fifth leading cause of cancer-related mortality worldwide, with stomach adenocarcinoma (STAD) being the predominant pathological type. Despite a decline in STAD incidence in recent years, factors such as an aging population may contribute to an increase in future cases. Current clinical management of STAD primarily involves surgical resection, radiation, chemotherapy, and emerging immune checkpoint blockade (ICB) therapies. However, the limited efficacy of ICB monotherapy in most patients with STAD highlights the need for novel therapeutic targets. This study investigated the role of versican (VCAN) in STAD. Comprehensive analysis of multiple databases revealed significantly higher VCAN expression in STAD tissues compared to normal tissues, correlating with poor patient prognosis. Single-cell analysis further identified VCAN as predominantly secreted by cancer-associated fibroblasts (CAFs), especially the pan-pCAF subtype. CAFs with elevated VCAN levels promoted the proliferation, migration, and invasion of high-stemness adenocarcinoma cells via the MDK-NCL and MIF-CD74-CD44 signaling pathways, while also enhancing immune evasion and self-renewal. These results position VCAN as a potential new therapeutic target for STAD.