Ratiometric Inclusion of Fibroblasts Promotes Both Castration-Resistant and Androgen-Dependent Tumorigenic...

Area of Science:

• Oncology
• Cancer Biology
• Biomaterials

Background:

• Prostate cancer (PCa) progression involves complex interactions between cancer cells and the tumor microenvironment.
• Stromal cells, particularly fibroblasts, are increasingly recognized for their role in supporting tumor growth and metastasis.
• Understanding these interactions is crucial for developing effective PCa therapies.

Purpose of the Study:

• To investigate the role of fibroblasts in prostate cancer progression using a novel 3D engineered prostate cancer tissue (EPCaT) model.
• To analyze how fibroblast coculture impacts androgen-dependent (ADPC) and castration-resistant (CPRC-ne) PCa cell behavior.
• To assess the clinical relevance of the EPCaT model by comparing it to patient data.

Main Methods:

• Establishment of a matrix-inclusive, 3D EPCaT model for direct coculture of PCa cells and fibroblasts.
• Analysis of PCa aggression markers, including matrix remodeling and cell proliferation, in EPCaTs.
• Bulk transcriptomic analysis to identify fibroblast-driven gene expression changes.
• Comparison of EPCaT gene expression profiles with the Cancer Genome Atlas (TCGA) PCa patient cohort.

Main Results:

• Fibroblast inclusion in EPCaTs significantly drives PCa aggression, matrix remodeling, and increased proliferation.
• A higher degree of aggression was observed with a lower ratio of fibroblasts to PCa cells.
• Fibroblast coculture promoted ADPC behavior similar to aggressive CPRC-ne, suggesting a role in disease state elevation and potential PCa subtype switching.
• Transcriptomic analysis revealed fibroblast-driven enrichment of hallmark gene sets associated with tumorigenic progression.
• EPCaT models showed similar gene set enrichment patterns to primary PCa tumors in the TCGA cohort, validating clinical relevance.

Conclusions:

• The 3D EPCaT model effectively mimics key aspects of prostate cancer progression.
• Fibroblasts play a critical ratiometric role in driving PCa aggression and potentially influencing the transition to more aggressive disease states.
• The EPCaT model serves as a valuable tool for future prostate cancer research and therapeutic development.