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Computational model of normal and cancer cell collective mechanics and migration

dos Santos Leite Ferreira, Ana Sofia (2017) Computational model of normal and cancer cell collective mechanics and migration. PhD thesis, University of Sheffield.

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Abstract

Changes in the biological behaviours of cell migration and sorting are associated with cancer. Mechanistic and quantitative understanding of the mechanics of these biological processes can promote the development of anti-cancer treatments. Computational models can be used as platforms to generate this understanding and to test drugs in-silico. The heterogeneity of cancer cells constitutes one of the main drawbacks in the development of anti-cancer drugs. Cell heterogeneity must be comprehended and regarded when developing anti-cancer drugs. This heterogeneity can be accounted for using computational modelling. In addition, now that measurement technologies allow the determination of the mechanical properties of normal and cancer cells, computational models with higher mechanical fidelity are possible. In this context, a quantitative and mechanistic computational model was developed in this work to investigate the role that the mechanical properties of cancer cells play in their migration and sorting. The individual cell properties: Young’s modulus, cell-cell adhesion and local microenvironment (neighbouring cells and position within the monolayer) were found to affect intercellular stress in the first hours following cell seeding. In addition, the presence of mechanically different normal and cancer cells in co-culture results in early sorting between them and higher variation of intercellular stress when comparing to normal and cancer monocultures. Quantitative mechanical thresholds for the sorting of migrating normal and cancer cells in co-culture were defined. Sorting depended primarily on differences in the traction force of normal and cancer cells and absolute cell-cell adhesion levels, followed by the differential adhesion of normal and cancer cells. The predictions supported an integrated mechanism for the sorting of normal and cancer cells. The model also predicted that different spatial distributions of cell mechanical properties can trigger different migration modes in cancer cell populations. This suggests that the plasticity of migration of cancer cell populations is related with the heterogeneity of cell mechanics. Since the sorting of normal and cancer cells in co-culture depends on the spatial distribution of their mechanical properties, mechanical thresholds for cell sorting should additionally depend on the cell microenvironment. The effect of microtubule stabilizers on sorting was tested in-silico accounting for the changes induced in the mechanical properties of cancer cells. Microtubule stabilizers were predicted to reverse both the mechanical and migration properties of cancer cells to properties similar to the ones of normal healthy cells. The sorting of normal and cancer cells, is thereby, reduced. This study shows that individual cell mechanical properties can explain a variety of population-scale measurements and behaviours. The results emphasize the importance of investigating the changes in cell mechanics that accompany malignant transformation and their role in cancer progression.

Item Type: Thesis (PhD)
Academic Units: The University of Sheffield > Faculty of Engineering (Sheffield) > Mechanical Engineering (Sheffield)
Identification Number/EthosID: uk.bl.ethos.736548
Depositing User: Miss Ana Sofia dos Santos Leite Ferreira
Date Deposited: 13 Mar 2018 11:36
Last Modified: 12 Oct 2018 09:52
URI: http://etheses.whiterose.ac.uk/id/eprint/19543

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