Modeling molecular and tissue dynamics in the human colonic crypt: an investigation into colon cancer development

Emerick, Brooks
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University of Delaware
The Wnt/β-catenin pathway plays a crucial role in stem cell renewal and differentiation in the normal human colonic crypt. The spatial dysregulation of β-catenin by the mutated tumor suppressor gene/protein APC in human colonic crypts is responsible for the initiation and growth of colorectal cancer. Therefore, the balance between β-catenin and APC gradients along the crypt axis determines its normal functionality and the mechanism that deregulates these biophysical gradients may give insight into the initiation of colorectal cancer. In this dissertation, we extend an existing model of the canonical Wnt pathway by considering a regulatory function that promotes APC synthesis within the cell. We analyze the effects of the feedback mechanism on the accumulation of the Wnt target protein, β-catenin. We also consider the dynamics of the system when exposed to a high concentration of the scaffolding protein Axin to gain insight into mammalian cell cultures and provide a framework for future extensions. Further, we investigate the dynamics of the APC regulatory mechanism at the tissue level by incorporating position dependent proliferation regions into a spatially one-dimensional model of the crypt. From here, we determine how APC mutations influence the spatial organization of cells by perturbing the underlying biochemical dynamics. We calibrate the model to biologically quantified data and produce results that describe both normal and abnormal crypt dynamics. We also explore a model to describe normal crypt fission, which provides a first look into a more detailed model of the human colonic crypt.