Micalet, Auxtine Emilie Marie; (2024) The Bio-Mechanical Signatures of Cancer Invasion Using a 3D In Vitro Model. Doctoral thesis (Ph.D), UCL (University College London).

Text Thesis Auxtine Micalet 15002120 corrected.pdf - Other Access restricted to UCL open access staff until 1 August 2024. Download (21MB)

Abstract

Introduction: Stiffness and mechanical signalling play a major role in tumorigenesis. As cancer cells invade into the stroma they induce matrix remodelling, either directly or through the recruitment of cancer-associated stromal cells, which further promotes cell invasiveness. Herein, 3D in vitro models were used to better understand the relationship between physical changes in the tumour micro-environment and cancer invasion.// Methods: The tumoroid model 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 changes in matrix stiffness by epithelial cancer cells were systematically characterized by atomic force microscopy (AFM) indentation tests. Associated matrix remodelling gene and protein expression were assessed, and inhibitory drug assays performed. Patientspecific primary cancer-associated fibroblasts (CAFs) were also later incorporated into the model.// Results and conclusion: When using a 3D model of biologically relevant stiffness (~3 kPa), less invasive cancer cells stiffened their tumour microenvironment whereas more aggressive epithelial cancer cells significantly softened it. Changes in stiffness were attributed to both cell-generated active forces as well as enzymatic ECM degradation and remodelling. It was confirmed that the highly invasive cancer cells expressed significantly higher matrix remodelling genes and proteins, such as uPA and MMPs. Targeting MMP and uPA activity through drug inhibition or CRISPR-Cas9 gene knockout limited matrix remodelling and significantly decreased cancer cell invasion. These results promote the idea of using mechano-based cancer therapies. Primary CAFs from six different patients exhibited remodelling trends (stiffening vs softening of the matrix) that correlated with the aggressiveness of the patients’ cancer.

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