Tissue-Engineered Brain-Mimetic Niches to Model Braintropic Triple-Negative Breast Cancer Metastasis

Brain metastases of triple-negative breast cancer (TNBC) rapidly progress, causing severe neurological decline with a median survival of less than 6 months. This tragic disease is often difficult to identify with sufficient time for treatment and is exacerbated by a lack of effective pharmacological intervention. Replicating the biochemical and mechanical properties of the premetastatic niche in vitro is a critical step in expediting the development of new therapeutics. However, a high-fidelity and reproducible model system is needed. To quantify the influence of a brain-mimetic microenvironment on brain metastatic TNBC, we encapsulated and cultured the TNBC cell line, MDA-MB-231 (P231), and its braintropic subline, MDA-MB-231-BrM2a-831 (BrM2a), in three premetastatic niches: a highly cell-adhesive and highly cell-degradable permissive niche, a highly adhesive but less degradable niche, and a nonadhesive but highly degradable niche. To mimic brain extracellular matrix, we functionalized the adhesive formulations with a brain-mimetic peptide cocktail and compared the cell responses to a "generic" RGDS-functionalization. This suite of conditions allowed us to investigate the influences of integrin-mediated adhesion, cell-mediated degradation, and cell type on the fate of P231s and BrM2as. Our data demonstrate that brain-mimetic adhesion has little to no impact on P231 phenotype, but the BrM2as display reduced viable cell density, reduced proliferation, and a higher proportion of both spherical clusters and spherical individual cells compared with the "generic" RGDS-functionalized niches. This suggests that brain-mimetic adhesion signaling encourages a rounded, less invasive phenotype in BrM2as. Modeling pathological processes usingadvanced, biomimetic in vitro models that better replicate in vivo cell phenotype have the potentialtoenhanceimprove the outcome of preclinical therapeutic testing.