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Title: Multiscale modelling of cancer cell motility
Author: Tozluoglu, M.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2013
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Cell motility is required for many biological processes, including cancer metastasis. The molecular requirements for migration and, the morphology of migrating cells, can vary considerably depending on matrix geometry. Therefore, predicting the optimal migration strategy or the effect of experimental perturbation is difficult. This thesis presents a computational model of single cell motility that encompasses flexible cell morphology, actin polymerisation based protrusions, cell cortex asymmetry, plasma membrane blebbing, local cortex heterogeneity at the protein level, cell–extracellular matrix adhesion, and varying extracellular matrix geometries. This computational model is used to explore the theoretical requirements for rapid migration in different matrix geometries. The analysis reveals that confinement of the cell within the extracellular matrix brings profound changes in the relationship between cortical contractility and cell velocity. In confined environments with discontinuity, the relationship between adhesion and cell velocity is fundamentally altered: adhesion becomes dispensable for a large range of gap sizes in between the extracellular matrix filaments. The utility of the model is shown by predicting cancer cell behaviour in vivo, in terms of both cell velocity and the morphology of the motile cell. Furthermore, the model is challenged to predict the effects of selected biochemical perturbations that alter i) cortical contractility, ii) cell-ECM adhesion, and iii) signalling between the cell-ECM adhesion sites and intracellular regulators of cell motility machinery. Multiphoton intravital imaging is used to verify bleb driven migration of melanoma, breast cancer cells, and, surprisingly, endothelial cells at tumour margins. Intravital imaging of melanoma verified model predictions on cell velocity, cell morphology, nucleus behaviour, and effects of anti-invasive interventions. The model succesfully predicted melanoma velocities in vitro and in vivo. Moreover, it successfully predicted the effects of anti-invasive interventions, showing all perturbations will result in significant reduction in cell velocity in vitro, whereas only perturbation of cortical contractility will affect cell velocity in vivo. The model also successfully predicted the interactions of the cell nucleus with the cell cortex and the cell morphology upon intervensions. Overall, from measure ment of rather simple variables in vitro, the model has been able to predict the in vivo response of three very different putative anti-invasive interventions.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available