Cell-cell signaling is a fundamental process of organisms during development, throughout their lifetime and in the course of cancer growth. In mammary tumors, tumor cells interact with macrophages via short-ranged signaling (paracrine) involving the growth factors EGF and CSF-1. This paracrine signaling enhances tumor cell invasion into surrounding tissues and blood vessels. Here I examined the roles that asymmetric receptor distribution, ligand secretion and gradient detection at the cellular level play in cancer cell invasion. Although there are already mathematical cell models that simulate cell movements in multicellular systems, none have included asymmetric distribution at the cell level. We incorporated non-uniform receptor density, ligand secretion and gradient detection in a 3-D individual cell-based model, that had been used to simulate the EGF/CSF-1 paracrine signaling in a tumor environment Our model can be used for any multicellular systems, where cells secrete and chemotax towards ligand gradients. Our model was optimized to reduce the computational cost of including non-uniform distributions at the sub-cellular level, when simulating thousands of interacting cells.I demonstrated that even when simulating thousands of cells, at scales much larger than the cell, non-uniformities at the single cell scale can significantly change the results. My simulations showed that non-uniform gradient detection dramatically enhanced the invasion of both tumor cells and macrophages and that non-uniform secretion significantly altered the invasion patterns of those cells. With no-flux boundary condition at the bottom, non-uniform secretion at either the front or back of the cell delayed the tumor cell invasion. However, secretion at the front enhanced macrophage invasion, while secretion at the back delayed it. Ultimately, fewer tumor cells invaded when secretion was at the front compared to uniform secretion and secretion at the back. These simulations helped us understand how the boundary conditions can potentially have a large impact on invasion profiles. They suggest that in vitro experiments with artificial boundary conditions may behave quite differently than the in vivo experiments that do not have no-flux boundary conditions. Overall, my simulations provide insight into how non-uniform receptor density, ligand secretion and gradient detection modify cell migration patterns. These simulations also suggest that it is very important to incorporate non-uniformities at the cell level when modelling chemically interacting multicellular systems.
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Thesis advisor: Palsson, Eirikur
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