3-D modelling of cell signalling and motility of tumour cells, epithelial tissues and zebrafish morphogenesis.

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Chemical and mechanical cell interactions operate throughout the lifespan of an organism and drive the transformation of a fertilized egg to a mature adult. An effective approach to understanding this complex transformation is through the development and use of mathematical models and computer simulations of these interactions. I propose to use a 3-D individual cell based model (ICBM) to study some of these basic interactions using three different model systems. Each study will answer questions related to the particular model system being investigated, but taken together, the research will advance our knowledge of how cell signaling, cell differentiation and cell adhesion work together during developmental processes to form mature structures. Moreover, such insights expand the applicability of the model to better understand other biological systems.***(1) The posterior lateral line (pLL) is a sensory system (for detecting water flow) formed early in fish development. I will use the ICBM to understand how polarization of the pLL primordium is set up in early stages of pLL development and, by modeling key signals (i.e. Wnt/FGF), I will determine how small signaling molecules (e.g. the chemokine SDF1a) drive collective migration toward the tail. I will also model the chemical interactions (e.g., Wnt, FGF, Notch) that lead to differentiation and establishment of the neuromast, a sensory organ of the fish, work that will help elucidate the underlying mechanism, which is shared among other vertebrates.***(2) Mammary tumor cells use an EGF/CSF-1 paracrine signaling system to signal to immune system cells called macrophages and coax them to open up passages into blood vessels. I will use my ICBM to model and to understand how this signaling operates and how it enhances tumor cell invasion. The model and predictions will be tested using data from both in vitro and in vivo experiments. My results will have implications for other paracrine signaling systems, such as between macrophages and connective tissue cells (e.g. fibroblasts) in wound healing.***(3) ‘EMT' is a process where a non-motile cell found in the tissues that line surfaces, such as the skin (i.e. an epithelial cell) undergoes multiple molecular changes, loses attachment to other cells and acquires a motile mesenchymal cell characteristic. EMTs play crucial roles in cell differentiation during development and are also involved in tissue repair, producing mesenchymal cells such as fibroblasts. I will use my ICBM to model and explore the changes in expression of adhesion and signaling molecules that are sufficient and necessary to initiate ETM in an epithelial cell layer. These mechanisms are important from a cell and developmental perspective, as well as from a disease prevention angle.**