Integrated analyses reveal prognostic markers associated with cancer-associated fibroblasts in oral squamous cell carcinoma

Abstract Objectives Oral squamous cell carcinoma (OSCC) is characterized by the presence of cancer-associated fibroblasts (CAFs) in its tumor microenvironment. This study aimed to investigate factors associated with stromal CAFs and develop a CAF-based classifier for prognosis and treatment prediction in OSCC. Methods mRNA expression profiles of mRNA and clinical data from 245 patients with OSCC were sourced from TCGA. Additional datasets (GSE41613, GSE65858, and GSE30784) comprising 97, 83, and 167 OSCC patients were also included. Weighted gene co-expression network analysis revealed genes linked to stromal CAFs, and a CAF-based risk signature was established. Primary OSCC tumor tissues were obtained from Nanjing Stomatological Hospital, and CAFs were isolated from fresh tumor samples. Expression of POSTN was confirmed in fibroblast and OSCC cell lines using reverse transcription-quantitative PCR and western blotting. Results Enhanced infiltration of CAFs correlated with a worse prognosis in OSCC patients. A four-gene prognostic signature including POSTN, TGFB3, PDGFRB, and COL6A2 was identified. Patients were categorized into high and low CAF risk groups based on median risk scores, with the high-risk group showing a significantly worse prognosis (p<0.001). High-risk OSCC patients exhibited increased susceptibility to BMS-754807, GSK269962A, and JQ1 treatments, while the response to radiotherapy and immunotherapy did not significantly differ. Fibroblast cell lines exhibited higher POSTN expression compared to OSCC cell lines and normal fibroblasts. Conclusions This study links increased CAF infiltration to a negative prognosis in OSCC patients. The four-gene prognostic signature holds potential clinical value, and identified markers may serve as therapeutic targets for OSCC.