Evaluating the impact chromosomal instability has on genomic evolution The research for my PhD is about understanding how chromosome instability impacts ongoing genomic evolution, including differences dependent on the mechanisms of CIN, as well as how these impact the response to therapy. I use High Grade Serous Ovarian Cancer, a cancer that has a extremely high occurrence of chemotherapy resistance and is a highly chromosomally unstable cancer type, as a model to investigate these questions. This includes using in vitro cell biology, syngeneic in vivo models and computational methods to interrogate genomic changes in different CIN environments.

Understanding the role of micronuclei in ongoing CIN in cancer, and their potential as a biomarker When either whole chromosomes or chromosome fragments fail to separate properly during mitosis, they form distinct bodies separate from the main nucleus of the daughter cells, called micronuclei (MN). While MN are a clear marker of CIN, they also have their own effects and can lead to further changes to the genome through dysfunctional DNA replication, accumulation of DNA damage, and even catastrophic events like chromosome shattering. They can even trigger an immune response which further modulates the disease. In this project, we aim to understand how micronuclei contribute to chromosomal instability in a disease context. To do so, we will characterize their behaviour in both cell lines and tumor samples, and will attempt to purify them to better understand their contents and function.

Evaluating the impact of chromosomal instability on cGAS-STING signaling My PhD project focuses on how ongoing chromosomal instability (CIN) may impact an important innate immune activating pathway called cGAS-STING. Normally, this pathway is activated by pathogens with a double-stranded DNA genome. However, we know that ongoing CIN may also activate this pathway via the production of micronuclei. Given this, we are interested in understanding how high levels of ongoing CIN may impact the functionality of this pathway. The primary role of cGAS-STING activation is to promote an immune response against an infected cell. Therefore, we are also interested in understanding the impact that high CIN may have on the wider tumour immune microenvironment, and how this may impact response to therapies. Specifically, we are working with models of high grade serous ovarian cancer, as this cancer type is characterised by extensive CIN.

Uncovering mechanisms converting replication stress to CNAs and CIN Replication Stress (RS) is extremely common among cancer cells but not nearly as prevalent in normal cells, therefore representing an interesting target for cancer treatment. Cancer cells have evolved mechanisms for tolerating and bypassing RS which are poorly understood and may be associated with the chromosomal instability (CIN) also frequently observed in cancer. The McClelland lab has previously uncovered that different types of RS generate different patterns of genomic alterations, hinting at the possibility that more than one mechanism may be behind this connection. My project uses CRISPR to manipulate the pathways involved in the RS response and apply single cell shallow whole genome sequencing to explore their potential role in genome maintenance.