Micalet, Auxtine; Pape, Judith; Bakkalci, Deniz; Javanmardi, Yousef; Hall, Chloe; Cheema, Umber; Moeendarbary, Emad; (2022) Evaluating the Impact of a Biomimetic Mechanical Environment on Cancer Invasion and Matrix Remodelling. Advanced Healthcare Materials , Article 2201749. 10.1002/adhm.202201749. (In press).

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Abstract

The stiffness of tumours and their host tissues is much higher than most hydrogels which are conventionally used to study in vitro cancer progression. The tumouroid assay is an engineered 3D in vitro tumour 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 was systematically characterised by atomic force microscopy (AFM) indentation tests. Less invasive epithelial cancer cells stiffen the tumour microenvironment while highly aggressive epithelial cancer cells showed significant softening of the tumour microenvironment. Changes in stiffness were attributed to both cell-generated active forces as well as ECM degradation and remodelling. The degradation was 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 level. Targeting MMP activity through broad-spectrum drug inhibition (BB-94) reversed the changes in stiffness and also decreased cancer cell invasion. These results promote the idea of using mechano-based cancer therapies such as MMP inhibition.

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