Wenbo Xu,1,2 Qian Niu,3 Kun Zhao,1,2 Haozhi Zhao,1,2 Long Zhang,1,2 Wenxuan Li,1,2 Hong Yan,3 Zhilong Dong1,2 

1Institute of Urology, Gansu Province Clinical Research Center for Urinary System Disease, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu, 730030, People’s Republic of China; 2Department of Urology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, People’s Republic of China; 3Department of Pathology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu, 730030, People’s Republic of China

Correspondence: Hong Yan, Department of Pathology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu, 730030, People’s Republic of China, Email 363891078@qq.com Zhilong Dong, Department of Urology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu, 730030, People’s Republic of China, Email dzl19780829@163.com

Background: Tumor stroma ratio (TSR) is a prognostic factor in various cancers, but its role in prostate adenocarcinoma (PRAD) remains unclear. This study investigates TSR’s prognostic value in PRAD using clinicopathological data, bulk/single-cell RNA sequencing to explore tumor-stroma interactions and identify therapeutic targets.
Methods: Two PRAD cohorts (The Cancer Genome Atlas cohort, TCGA; Lanzhou University Second Hospital, LUSH) were analyzed for TSR associations with clinicopathological features and biochemical recurrence (BCR). TSR was assessed via digital image analysis and expert pathologist review. Publicly available bulk/single-cell RNA sequencing data were analyzed to identify TSR-associated genes and predict drug targets, pathways, and immunotherapy responses. Quantitative real-time PCR validated mRNA expression. In vitro assays assessed cell proliferation, growth, and migration, while in vivo xenograft assays validated BGN’s role in promoting tumorigenesis.
Results: TSR significantly correlated with clinicopathological features (age, Gleason score, stage, seminal vesicle invasion, BCR) in both TCGA (n = 453) and LUSH (n = 320) cohorts. High TSR independently predicted BCR in multivariable Cox regression. High TSR was associated with copy number variations, differentially expressed miRNAs/transcription factors, and metabolic pathways. Predicted anti-cancer drug targets, like Ki8751, showed potential benefit in high-TSR patients. High TSR may correlate with poor immunotherapy response. Notably, downregulation of BGN in cancer-associated fibroblasts (CAFs) significantly suppressed cell proliferation, migration, and invasion in vitro, and in vivo xenograft assays confirmed that BGN downregulation inhibited tumor growth.
Conclusion: This study highlights TSR’s prognostic significance in prostate cancer and its association with adverse clinical outcomes and complex tumor-stroma interactions, identifying BGN, a stromal cell-related gene, as a potential therapeutic target for CAFs. However, these findings are limited by the retrospective design, necessitating prospective validation.

Keywords: prostate cancer, tumor-stroma ratio, genomic, single-cell RNA sequencing, prognosis