Toward More Translational Tumor Models: Breast dECM-Based 3D Systems Capture Native Microenvironmental Cues

Current 3D tumor models for aggressive breast cancers inadequately recapitulate the native tumor microenvironment (TME), leading to poor translational potential. There is a critical need for models capable of mimicking the unique biochemical signals present in the TME. To address this gap, breast tissue and a patient derived xenograft tumor were decellularized and processed to produce breast tissue and tumor decellularized ECM (dECM). Decellularized breast tissue histology confirmed complete cellular removal and maintained extracellular matrix (ECM). Further, DNA content was significantly reduced and ECM composition (POSTN, COLI, FN1) retained. Breast dECM was incorporated (0, 5, 10, and 20 µg/mL) with triple negative breast cancer cell lines to form spheroids. Imaging and histology demonstrated that cells in low dECM (5 and 10 µg/mL) formed compact singular spheres while higher dECM concentrations (20 and 50 µg/mL) resulted in cells concentrated on the outer edge of the sphere and irregular sphere circularity. RNA-sequencing of cells seeded in dECM demonstrated gene changes mediated by both dECM inclusion in spheroids and the composition of dECM. High-density tumor dECM enhanced genes associated with metastasis while high-density breast dECM enhanced tumor suppressors and anti-metastasis genes. These findings indicate dECM as a translational model with enhanced TME inclusion.