Joyce, Holly Louise; (2024) Structural components of tumour cells interact and adapt to confer mechanical properties favourable for tumorigenesis. Doctoral thesis (Ph.D), UCL (University College London).

Text Joyce, Holly_Thesis for Submission - Holly Joyce 1.pdf - Submitted Version Access restricted to UCL open access staff until 1 August 2025. Download (50MB)

Abstract

Cancer prognosis has long been known to correlate with tumour stiffness. Studies to date suggest this may be due to limiting treatment response and encouraging tumourigenic behaviours (metastasis and invasion). Advances in imaging enable the assessment of tumour mechanical properties in the clinic. However, as the cellular determinants of bulk tumour modulus are incompletely described, interpretation of image data in the context of pathology is limited and the development of targeted treatment hindered. The bulk of research to date focusses on extracellular elements within the tumour microenvironment (TME), neglecting the contribution of core tumour constituents: cancer cells. To understand how the prototypical structural elements of tumour cells determine tumour stiffness, I first undertook a series of in vitro experiments using A431 squamous cell carcinoma (SCC) cell lines modified to mimic changes common to epithelial-mesenchymal transition. CRISPR / Cas9 was used to knock-out genes for force-generating non-muscle myosin IIa (MYH9) and junctional a-catenin (CTNNA1) proteins. Constitutively active Yes-associated protein (YAP) was inserted via retroviral editing. Cell and aggregate stiffness as assessed by atomic force microscopy showed elasticity was enhanced and fluidity decreased in wildtype cellular aggregates with adherens junctions and myosin intact. Attempts to validate these findings in vivo with mouse tumour models, suggest the role of tumour cells in maintaining stiffness may be overshadowed by forces generated by interstitial fluid or other cells within the TME, such as cancer-associated fibroblasts. The functional impact of aggregate stiffness, or resistance to compression, showed survival and proliferation in these populations. Gene expression profiles activated by compression is not dependent on junctional phenotype and may represent a sterile response to injury. Further, the compressive response of A431 SCC cells may be independent of well-known mechanotransduction pathways, including ERK-mitogen-activated protein kinase, YAP, and Piezo1.

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