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Albert Rübben
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Proceedings Papers
. isal2019, ALIFE 2019: The 2019 Conference on Artificial Life195-202, (July 29–August 2, 2019) doi: 10.1162/isal_a_00161
Abstract
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Colorectal cancer (CRC) is the second most common tumour in the world (Bray, 2018). It has been proposed that morbidity and mortality could be mitigated by screening methods that identify key genetic mutations in the DNA of a patient’s biosample (Traverso, 2002). However, for this to work, a theoretical understanding of the most likely mutations that initiate malignant transformation, and how they affect subsequent microevolution, is needed. Specifically, we hypothesise that there is a CRC-proliferative mutation that is more likely to be initially fixated in the crypt . To investigate this, we developed an agent-based model of cells in the colon crypt that shows emergent biological homeostasis at the tissue level from the cellular and molecular interactions. We equipped each of the cells with a molecular gene network which, in their wildtype state, regulates homeostasis in the crypt and recapitulates known behaviour. We identified and modelled key genes implicated in CRC which, when mutated, alter the rate of death and division of cells. We used this model to study the biological first principles of the fixation of mutations, offering key spatial and temporal understanding of this process. We discuss the impact and clinical relevance of proliferative genetic mutations in isolation, pointing to the KRAS gene as a likely mutation to be initially fixed in the crypt.
Proceedings Papers
. alife2018, ALIFE 2018: The 2018 Conference on Artificial Life420-427, (July 23–27, 2018) doi: 10.1162/isal_a_00080
Abstract
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Intestinal glands in the small intestine and colon, or intestine crypts, are an important example of tissue homeostasis regulated by the extracellular environment. The crypts are invaginated structures made of a layer of cells that help absorb nutrients from passing food. However, they are continuously worn away by this process and are being continually renovated by stem cells at the bottom of the crypt. These stem cells divide to replace worn cells and may even displace other stem cells so that at a given time the whole crypt becomes monoclonal- a descendant of one single stem cell. From a theoretical standpoint, the time it takes to reach monoclonality is crucial to the understanding of colorectal cancer (CRC) as it offers a key metric for the establishment of cancer initiating mutations; however, the biggest biological contributor to this feature is highly debated. Three key hypotheses have been put forwards, which we investigated with ALife methods. We have abstracted key biological features and modelled them in a bottom-up Agent-Based Model that allowed us to study the biological first principles that rule the fixation of mutations, offering key spatial and temporal understanding of this process. Our results show that the number of basal stem cells have a direct influence on the fixations of mutations and suggesting a lesser role for extracellular influences, while proposing the existence of a threshold to the contribution of cell side displacement