Matrix and stromal cues cooperatively regulate dormancy-like states of prostate cancer in a dual-niche metastatic model.

Prostate cancer (PCa) exhibits a strong tropism for bone, where interactions with the bone microenvironment critically influence metastatic progression and therapeutic resistance. However, the complexity of tumor-bone interactions remains difficult to model in conventional systems. Here, we developed an engineered dual-niche platform that recapitulates both primary tumor and bone metastatic microenvironments using tunable extracellular matrix mechanics, bone matrix-derived soluble factors (BMSFs), and bone marrow stromal cells (BMSCs). Within the primary tumor-like niche, increasing matrix stiffness suppressed LNCaP-C4-2B cell proliferation while promoting cell dissemination. In contrast, BMSFs exerted a dual effect by inhibiting tumor proliferation while inducing osteomimetic differentiation through upregulation of Runx2 and Cbfa1. In vivo, BMSFs elicited inflammatory and vascular responses associated with suppressed tumor expansion. Notably, BMSCs primed with bone matrix factors markedly enhanced PCa cell proliferation and migration in vitro and accelerated tumor formation in vivo, revealing a stromal-driven pro-tumorigenic mechanism. Together, these findings uncover a functional dichotomy within the bone microenvironment, in which bone matrix-derived factors promote tumor adaptation and dormancy, while stromal components drive tumor expansion. This engineered dual-niche model provides a versatile platform to dissect microenvironment-specific mechanisms and may inform strategies targeting bone metastatic progression in prostate cancer.