Engineering Tumor Stroma Morphogenesis Using Dynamic Cell-Matrix Spheroid Assembly.

Area of Science:

• Biomedical Engineering
• Cancer Biology
• Extracellular Matrix Research

Background:

• The tumor microenvironment's complex extracellular matrix (ECM) is crucial for cancer progression but difficult to replicate in vitro.
• Existing in vitro models often fail to capture the intricate interactions between tumor cells and their native ECM.

Purpose of the Study:

• To engineer a novel 3D MatriSpheres system that recapitulates the native tumor microenvironment.
• To investigate how self-assembled ECM influences colorectal cancer (CRC) cell phenotype and malignancy.

Main Methods:

• Developed a self-assembly system using decellularized small intestine submucosa (SIS) ECM to create 3D MatriSpheres with CRC cells.
• Utilized proteomic analysis to compare SIS ECM with traditional Matrigel for CRC homology.
• Employed single-cell RNA sequencing to analyze transcriptional changes in tumor cells within the 3D model.

Main Results:

• 3D CRC MatriSpheres were successfully created using SIS ECM, showing greater proteomic homology to native CRC ECM than Matrigel.
• CRC cells actively organized and concentrated SIS ECM, forming ECM-rich 3D stroma-like regions within 4-5 days.
• ECM organization and cues modulated cancer cell programs related to malignancy, lipid metabolism, and immunoregulation, consistent with in vivo findings.

Conclusions:

• The self-assembly system enables scalable, spontaneous engineering of ECM-rich 3D tumor models.
• This approach stimulates tumor-specific tissue morphogenesis, integrating cancer cell and ECM complexities.
• The 3D MatriSpheres model shows potential for advancing precision medicine by better reflecting in vivo tumor biology.