Gregory, Stephen LennoxO'Keefe, Louise VeronicaLiu, Dawei2017-07-052017-07-052016http://hdl.handle.net/2440/106415Most human solid cancers show Chromosomal Instability (CIN) in which cancer cells show a higher rate of gain or loss of whole chromosomes or large chromosomal fragments. CIN is associated with the progression of tumorigenesis, the development of cancer drug resistance and the poor prognosis. Since CIN is a hallmark of cancers and not common in normal cells, it has been proposed that CIN is targetable for cancer therapy. In order to target CIN for cancer treatment, there is a need to determine the signalling pathways which enable cells to tolerate CIN. The aim of this study is to identify signalling pathways activated in response to CIN which could potentially be targeted to specifically kill CIN cells. Using Drosophila as the model organism to study CIN (Chapter 2), we found that CIN cells are specifically sensitive to metabolic disruption as the depletion of metabolic genes involved in glycolysis, tricarboxylic acid cycle and oxidative stress response led to high levels of oxidative stress, DNA damage and apoptosis only in CIN cells (Chapter 3). Consistent with its role in stress responses, in the subsequent study, we found that the autophagy pathway is robustly activated in CIN cells and autophagy inhibition can specifically kill CIN cells. We also found that autophagy activation removes defective mitochondria in CIN cell which gives tolerance to CIN in proliferating cells (Chapter 4). We also found a systemic immune signalling activation in Drosophila larvae when CIN was induced in the engrailed region of wing discs. Moreover, we found that the immune signalling Toll pathway is also activated within CIN cells and manipulation of Toll pathway could affect the survival of CIN cells. We proposed that signals released from CIN cells such as reactive oxygen species (ROS) could trigger a local Toll pathway activation in CIN tissue which in turn recruits Drosophila blood cells (hemocytes) to the surface of the CIN tissues. These recruited hemocytes then initiate apoptosis in the CIN cell through the TNFα/JNK pathway (Chapter 5). In conclusion, our studies demonstrated that CIN leads to a variety of consequences in cells: several signalling pathways including metabolic pathways, autophagy and Toll signalling are activated in response to CIN stresses. Understanding the mechanisms of these pathways responding to CIN will provide insights into designing cancer specific drug targets and ultimately contribute to cancer treatment.cancerchromosomal instabilityDNA damagedrosophilacell cyclemetabolismROSinnate immune responsetoll signallingautophagymitophagyResearch by PublicationTheses10.4225/55/595c401158155