Biomimetic bone niche reconstructs proliferation-inhibited and therapy-resistant bone-metastatic prostate cancer.

Abstract

Prostate cancer bone metastases often harbor a rare subset of tumor cells with suppressed proliferation, contributing to therapy resistance and disease relapse. However, the lack of physiologically relevant <i>in vitro</i> models has hindered mechanistic and therapeutic advances. Here, we engineered a 3D bone-like microenvironment by integrating calcium phosphate scaffolds, decellularized extracellular matrix (dECM), mesenchymal stem cells (MSCs), and osteoblasts. This biomimetic niche induced a proliferation-inhibited state in prostate cancer cells, closely mirroring transcriptomic signatures identified from patient-derived single-cell RNA sequencing datasets. Tumor cells in this niche also displayed enzalutamide resistance, accompanied by metabolic reprogramming and activation of pro-survival signaling. This platform provides a clinically relevant tool for modeling bone metastatic prostate cancer and accelerating the development of therapies targeting resistant tumor states.