Initial stages of bone colonization by breast cancer cells are critical for metastasis, but current in vitro models cannot decipher the microenvironmental cues involved. Therefore, a biphasic hydrogel model system is designed that recapitulates structural, biophysical, and biochemical components of the bone microenvironment to replicate early metastasis events. Breast cancer cells embedded within a glycosaminoglycan-based nanoporous hydrogel phase are traced as they colonize a directly adjacent macroporous cryogel compartment, precisely and selectively equipped with specific bone-like biomolecular signals and/or solution-deposited mineral crystals. Microscopic monitoring of the spatiotemporal cancer cell distributions yields colonization profiles that display the correlated effects of cell invasion, matrix interaction, and proliferation. MDA-MB-231 cells, but not MCF-7 cells, rapidly infiltrate the cryogel compartment at rates depending on the cross-linking degree of the hydrogel phase. Cryogel functionalization with adhesion-mediating peptide ligands enhances matrix interactions and survival/proliferation of the MDA-MB-231 cells. When combined with cryogel-released stromal cell-derived factor 1 (SDF-1), survival/proliferation are further amplified and additionally MDA-MB-231 cell invasion is promoted. The presence of deposited bone-like mineral strongly impedes these responses and is accompanied by characteristic alterations in distinct cellular gene-expression programs. The reported methodology may not only provide further mechanistic insights into early bone metastasis, but also facilitate the screening of anti-metastatic drugs.