A regular feature of cells in most tumours is an abnormal number of chromosomes – a feature known as aneuploidy. A key mechanism towards this state is whole chromosome mis-segregation (CMS), whose role in cancer is still debated. For a long time, CMS was considered a side effect of oncogenesis, however recent research suggests instead a role as a key initiating driver of malignant transformation. Specifically, whether the mechanism of CMS can lead to the kind of mutational signature observed in early stage tumours is unknown. Furthermore, the signalling pathways themselves are still being elucidated, and the impact that these different mechanisms have on the network are yet not defined. Because of the high biological complexity, experimental limitations and overall uncertainty, ALife methods are well suited to untangle the role of CMS and shed light on its role in oncogenesis. Here we investigate the effects that CMS and point mutation have on a biologically inspired genome, implemented in silico though a gene-regulatory network (GRN) within an agent-based model (ABM). Importantly, the implementation aims to mimic real biology to facilitate possible emergent features. Each cell is equipped with chromosomes containing abstractions of key interconnected genes that are known to play a role in many cancers. We compare the effects of random mutations, where a gene is functionally altered, against CMS, where many genes are lost or gained simultaneously. Our results show that CMS is a viable mechanism for oncogenesis. Comparing CMS with the more traditional view of mutation accumulation, we show that both share similar emergent phenotypes, but that they are genotypically different. We highlight that loss of tumour suppression by either means might be the first step towards oncogenesis, and conclude that cancers probably utilize these two mechanisms in tandem. Finally, we propose that measurements of these aberrations could help to better characterize the evolution of tumours.

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.

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