Evaluating the Impact of a Biomimetic Mechanical Environment on Cancer Invasion and Matrix Remodeling

Abstract

The stiffness of tumors and their host tissues is much higher than most hydrogels, which are conventionally used to study in vitro cancer progression. The tumoroid assay is an engineered 3D in vitro tumor model that allows investigation of cancer cell invasion in an environment that is biomimetic in terms of extracellular matrix (ECM) composition and stiffness. Using this model, the change in matrix stiffness by epithelial colorectal cancer cells is systematically characterized by atomic force microscopy indentation tests. Less invasive epithelial cancer cells stiffen the tumor microenvironment while highly aggressive epithelial cancer cells show significant softening of the tumor microenvironment. Changes in stiffness are attributed to both cell‐generated active forces as well as ECM degradation and remodeling. The degradation is in part attributed to the enzymatic activity of matrix metalloproteinases (MMPs) as demonstrated by the significant expression of MMP‐2 and MMP‐9 at both gene and protein levels. Targeting MMP activity through broad‐spectrum drug inhibition (BB‐94) reverses the changes in stiffness and also decreases cancer cell invasion. These results promote the idea of using mechano‐based cancer therapies such as MMP inhibition.

The role of Piezo1 mechanotransduction in high-grade serous ovarian cancer: Insights from an in vitro model of collective detachment

“…The model system used in this work is a PAA gel; therefore, its stiffness was not susceptible to MMP degradation and softening. It was recently shown that a compressed collagen gel (elastic modulus, 4 kPa) treated with recombinant MMP-1 (800 ng/ml) softened from 4 to 1 kPa over 5 hours ( 56 ). While this would suggest we could see substantial softening, we note that the highest concentration of MMP-1 observed in our cultures was on the order of 10 ng/ml (80-fold less), which suggests that this effect would be slower or lessened—particularly as the stiffness in metastatic HGSOC is an order of magnitude higher.…”

Emergent mechanical control of vascular morphogenesis

“…Having established the emergence of enhanced tissue stiffening, we investigated the possible cause of the stiffening. Specifically, we constructed a model to evaluate the contribution of active forces applied by cells and changes in ECM mechanics (41)(42)(43)(44). This highlighted that cell-generated forces could play a major role in the emergent stiffening of the vascular networks (fig.…”

Endothelium and Subendothelial Matrix Mechanics Modulate Cancer Cell Transendothelial Migration

“…Furthermore, ECM properties can be tuned to have stiffnesses similar to human tissues, such as breast, bone marrow, and brain, which are all common sites of breast cancer extravasation. [ 41 , 42 , 43 , 44 ]…”