A 3D Biofabricated Disease Model Mimicking the Brain Extracellular Matrix Suitable to Characterize Intrinsic Neuronal Network Alterations in the Presence of a Breast Tumor Disseminated to the Brain

A 3D cellular breast-to-brain tumor model is developed using thiolated-hyaluronic-acid-based hydrogel cross-linked with extracellular matrix (ECM) proteins collagen type IV, laminin-211, and fibronectin to mimic the native-brain ECM. The 3D model resembles the basement membrane around the blood vessels, which surrounds the brain parenchyma and is important for initial survival of breast tumor cells passing the blood–brain barrier. Brain metastasis in breast cancer patients is one of the leading causes of mortality. While, supplemented ECM proteins do not significantly alter the nominal stress response of the hydrogel, the analysis of the tumor microenvironment interactions displays a significant impact of neuron and astrocyte presence on ECM secretion. Additional ECM supplementation does not further promote proliferation of breast tumor cells in a natively extrinsic surrounding. MDA-MB-361 exhibits numerous contacts with collagen type IV. Neuronal network activity is significantly increased in the presence of MDA-MB-361 cells. Increased colocalization of the vesicular glutamate transporter 1 on neurons and connexin 43 on astrocytes argues for beneficial interactions for the tumor's intrinsic proliferation capacity via pseudosynaptic contacts and gap junctions as shown in vivo. Such 3D disease models represent a suitable platform to further investigate tumor treatment options in a systematic manner.