Matrix stiffness regulates microvesicle-induced fibroblast activation.

Area of Science:

• Cancer Biology
• Biomaterials Science
• Cellular Mechanobiology

Background:

• Cancer cell-derived extracellular vesicles, specifically microvesicles, are known to alter recipient cell behavior.
• Stromal cell differentiation into cancer-supporting states is influenced by these microvesicles.
• The impact of tumor microenvironment physical properties on fibroblast response to microvesicles is poorly understood.

Purpose of the Study:

• To investigate how the mechanical properties of the tumor microenvironment affect fibroblast phenotype in response to cancer cell-derived microvesicles.
• To determine if substrate stiffness influences microvesicle-induced fibroblast activation.

Main Methods:

• Utilized microvesicles derived from highly malignant breast cancer cells.
• Employed synthetic substrates with varying stiffness to mimic tumor and tumor stroma.
• Assessed fibroblast spreading, alpha-smooth muscle actin expression, proliferation, traction force, and collagen gel compaction.

Main Results:

• Cancer cell microvesicles significantly increased fibroblast spreading, alpha-smooth muscle actin expression, proliferation, traction force, and collagen gel compaction.
• These phenotypic changes were observed exclusively on stiff matrices simulating tumor periphery stiffness.
• The observed effects were dependent on the specific cell type releasing the microvesicles.

Conclusions:

• The physical properties of the tumor microenvironment, particularly stiffness, regulate the activation of fibroblasts by cancer cell-derived microvesicles.
• Stiff matrices are required for microvesicle-induced fibroblast activation.
• Microvesicles may exert a stronger influence on fibroblasts at the tumor periphery, potentially promoting cancer progression.