BGN marks cancer-associated fibroblast activation and extracellular matrix remodeling in HNSCC

Biglycan (BGN) is an important component of the extracellular matrix (ECM). Using an integrated analysis of TCGA bulk RNA-sequencing, single-cell RNA-sequencing, and spatial transcriptomic datasets, we systematically characterized the expression patterns, prognostic significance, and biological roles of BGN in head and neck squamous cell carcinoma (HNSCC). Western blotting, immunohistochemistry, and survival analyses in independent clinical cohorts further validated the expression pattern, abundance, and prognostic significance of BGN. The biological role of BGN was further investigated using in vitro tumor cell-cancer-associated fibroblasts (CAFs) co-culture systems, BGN knockdown, and subsequent phenotypic assays. Here, BGN was significantly upregulated in HNSCC tissues, and elevated BGN expression was associated with poorer patient prognosis. Higher BGN expression was also associated with increased mesenchymal scores, enrichment of pathways related to CAF activation, ECM remodeling, and epithelial-mesenchymal transition (EMT), as well as potentially reduced sensitivity to commonly used chemotherapeutic agents. Single-cell transcriptomic analysis revealed that BGN was predominantly expressed by CAFs, with BGN-positive (BGN+) CAFs exhibiting markedly enhanced ECM remodeling activity and greater potential for intercellular communication. Spatial transcriptomic analysis further demonstrated that BGN-high spots were preferentially localized within the stromal matrix and distant from the tumor core. Functionally, tumor cells co-cultured with BGN-knockdown CAFs exhibited reduced proliferation, colony-forming capacity, invasion, and migration, accompanied by suppression of the EMT phenotype. Collectively, these findings suggest that BGN may serve as a biomarker of an ECM/stromal remodeling-dominant CAF state in HNSCC and represent a potential therapeutic target for HNSCC.