Loss of biomechanical features reveals smooth muscle disruption and disease progression in prostate cancer.

[BACKGROUND] Biomechanical features show notable heterogeneity in tumor risk stratification, yet their role in prostate cancer (PCa) progression remains unclear. This study aimed to elucidate the role and underlying mechanism of biomechanical features in PCa progression.

[METHODS] We integrated transcriptomic data from 1693 PCa patients across ten public cohorts and single-cell RNA sequencing (scRNA-seq) data from 19 PCa samples to define biomechanical subtypes. RT-qPCR was used to assess the impact of mechanical stimulation on malignant phenotypes. Biomechanical regulatory genes (BMRGs) were identified using consensus clustering and Weighted Gene Co-expression Network Analysis (WGCNA). A prognostic index (MRPX) was developed using machine learning. Immune infiltration and drug sensitivity analyses were conducted to assess the clinical utility of MRPX in guiding precision therapy. A co-culture model was employed to assess the impact of COL5A1-positive fibroblasts on the metastatic potential of PCa cells.

[RESULTS] Loss of biomechanical features was associated with smooth muscle disruption and PCa progression. In vitro mechanical stimulation suppressed EMT-related gene expression in PC-3 cells. WGCNA identified 137 hub BMRGs, from which MRPX was constructed. MRPX demonstrated strong generalizability in predicting PCa progression and effectively stratified patient responses to both immunotherapy and chemotherapy. Elevated MRPX was associated with smooth muscle disruption, which linked MRPX to extracapsular extension (ECE) and enhanced metastatic potential. Mechanistically, COL5A1 was closely linked to PCa progression, and CellChat analysis indicated that COL5A1⁺ fibroblasts contribute to shaping an aggressive tumor microenvironment. Co-culture experiments confirmed a marked upregulation of COL5A1 in cancer-associated fibroblasts (CAFs). Furthermore, silencing of COL5A1 significantly attenuated the ability of CAFs to promote the metastatic potential of PC-3 cells.

[CONCLUSIONS] This study establishes MRPX as a robust biomarker for prognostic stratification and therapeutic guidance in PCa, offering new insights into biomechanical regulation of tumor progression and providing a potential avenue for precision oncology.