A 3D-bioprinted osteogenic niche model reveals bone microenvironment-driven malignant phenotypes in prostate cancer

Prostate cancer (PCa) is one of the most prevalent malignancies in men and frequently progresses to bone metastasis. Understanding the interactions between PCa cells and the bone microenvironment, as well as their impact on therapeutic response, is therefore of critical clinical relevance.

This study aimed to investigate the effects of the osteogenic microenvironment on prostate cancer cells by constructing three-dimensional (3D) bioprinted in vitro co-culture models, and to evaluate how the osteogenic niche influences tumor malignant phenotypes.

This study employed extrusion-based 3D bioprinting (3DP) to construct in vitro co-culture models of the PCa osteogenic microenvironment. Two 3D-PCa models based on LNCaP and PC-3 cells were each co-cultured with osteogenically differentiated adipose-derived stem cells (ADSCs) to generate corresponding osteogenic niche models. Tumor phenotypes and drug responses were evaluated using functional assays, histological and immunofluorescence analyses, molecular profiling, and RNA sequencing.

The 3D bioprinted constructs exhibited structural stability and high reproducibility, providing a 3D growth environment that mimics key aspects of the in vivo tumor niche. The 3D-PCa models showed enhanced drug resistance, invasive potential, and adaptation to androgen-deprivation. Meanwhile, ADSCs exhibited robust osteogenic differentiation within 3D scaffolds. Under co-culture conditions, 3D-PCa cells exhibited enhanced malignant-like phenotypes, including increased proliferation and reduced drug sensitivity. Multi-level analyses further indicated that these phenotypic changes were associated with coordinated activation of epithelial-mesenchymal transition (EMT)-, hypoxia-, and mitogen-activated protein kinase (MAPK)-related signaling programs, accompanied by alterations in drug transporter expression and cell cycle distribution.

The 3D co-culture model provides a biomimetic platform for simulating the PCa bone-metastatic microenvironment. This system enables investigation of the effects of the osteogenic niche on tumor behavior and therapeutic responses, and may serve as a useful tool for preclinical drug screening and evaluation of combination treatment strategies for bone-metastatic prostate cancer.