Patient-specific colorectal-cancer-associated fibroblasts modulate tumor microenvironment mechanics.

ABSTRACT

Cancer-associated fibroblasts (CAFs) play a major role in reorganizing the physical tumor micro-environment and changing tissue stiffness. Herein, using an engineered three-dimensional (3D) model that mimics the tumor's native biomechanical environment, we characterized the changes in matrix stiffness caused by six patient-specific colorectal CAF populations. After 21 days of culture, atomic force microscopy (AFM) was performed to precisely measure the local changes in tissue stiffness. Each CAF population exhibited heterogeneity in remodeling capabilities, with some patient-derived cells stiffening the matrix and others softening it. Tissue stiffening was mainly attributed to active contraction of the matrix by the cells, whereas the softening was due to enzymatic activity of matrix-cleaving proteins. This measured heterogeneity was lost when the CAFs were cocultured with colorectal cancer cells, as all samples significantly soften the tissue. The interplay between cancer cells and CAFs was critical as it altered any heterogeneity exhibited by CAFs alone.