Investigating the Origins of Cancer in the Intestinal Crypt with a Gene Network Agent Based Hybrid Model

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

Modelling Chromosome Missegregation in Tumour Evolution

Cancer is a disease in which the controls that usually ensure the coordinated behaviour of individual cells break down. This rarely happens all at once. Instead, the clone of cells that grows into a developing tumour is under high selection pressure, leading to the evolution of a complex and diverse population of related cells that have accumulated a wide range of genetic defects. One of the most evident but poorly characterized of these genetic abnormalities is a disorder in the number of chromosomes, or aneuploidy. Aneuploidy can arise though several different mechanisms. The project explores one such mechanism - chromosome missegregation during cell division- and its role in oncogenesis. To address the role that chromosome missegregation may have in the development of cancer a computational model was devised. We then defined the behaviour of individual cells, their genomes and a tissue niche, which could be used in simulations to explore the different types of cell behaviour likely to arise as the result of chromosome missegregation. This model was then used to better understand how defects in chromosome segregation affect cancer development and tumour evolution during cancer therapy. In stochastic simulations, chromosome missegregation events at cell division lead to the generation of a diverse population of aneuploid clones that over time exhibit hyperplastic growth. Significantly, the course of cancer evolution depends on genetic linkage, as the structure of chromosomes lost or gained through missegregation events and the level of genetic instability function in tandem to determine whether tumour growth is driven primarily by the loss of tumour suppressors or by the overexpression of oncogenes. As a result, simulated cancers diff er in their level of genetic stability and in their growth rates. We then used this system to investigate the consequences of these differences in tumour heterogeneity for anti¬cancer therapies based on surgery and anti-mitotic drugs that selectively target proliferating cells. Results show that simulated treatments induce a transient delay in tumour growth, and reveal a significant difference in the efficacy of different therapy regimes in treating genetically stable and unstable tumours. These data support clinical observations in which a poor prognosis is correlated with a high level of chromosome missegregation. However, simulations run in parallel also exhibit a wide range of behaviours, and the response of individual simulations (equivalent to single tumours) to anti-cancer therapy prove extremely variable. The model therefore highlights the difficulties of predicting the outcome of a given anti-cancer treatment, even in cases in which it is possible to determine the genotype of the entire set of cells within the developing tumour