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

Area of Science:

• Biomaterials Science
• Cancer Biology
• Tissue Engineering

Background:

• Current 3D tumor models for aggressive breast cancers fail to accurately replicate the native tumor microenvironment (TME).
• This limitation leads to poor translational potential in preclinical research.
• There is a critical need for advanced models that mimic TME biochemical signals.

Purpose of the Study:

• To develop novel 3D breast cancer models using decellularized extracellular matrices (dECM).
• To investigate the impact of breast and tumor-specific dECM on cancer cell behavior and gene expression.
• To enhance the recapitulation of the TME in 3D breast cancer models.

Main Methods:

• Decellularization of breast tissue and patient-derived xenograft tumors to obtain dECM.
• Incorporation of breast dECM into triple-negative breast cancer cell lines to form spheroids at varying concentrations (0-50 µg/mL).
• Histological analysis, DNA content quantification, and RNA-sequencing to assess ECM integrity, cellular organization, and gene expression changes.

Main Results:

• Histology confirmed complete cellular removal and ECM retention, with reduced DNA content.
• Low dECM concentrations (5-10 µg/mL) promoted compact spheroid formation, while higher concentrations (20-50 µg/mL) led to peripheral cell distribution and irregular shapes.
• RNA-sequencing revealed that dECM composition influenced gene expression; tumor dECM upregulated metastasis-associated genes, while breast dECM enhanced tumor suppressors and anti-metastasis genes.

Conclusions:

• Decellularized extracellular matrices (dECM) can be successfully produced from breast tissue and tumors, retaining key ECM components.
• dECM incorporation into 3D breast cancer models provides critical physiological cues that influence cell morphology and gene expression.
• These dECM-based 3D models offer a more accurate representation of the TME, holding promise for improved breast cancer research and drug development.