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Type: Theses
Title: The investigation of signalling pathways in response to chromosomal instability
Author: Liu, Dawei
Issue Date: 2016
School/Discipline: School of Biological Sciences
Abstract: Most 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.
Advisor: Gregory, Stephen Lennox
O'Keefe, Louise Veronica
Dissertation Note: Thesis (Ph.D.) (Research by Publication) -- University of Adelaide, School of Biological Sciences, 2016.
Keywords: cancer
chromosomal instability
DNA damage
drosophila
cell cycle
metabolism
ROS
innate immune response
toll signalling
autophagy
mitophagy
Research by Publication
Provenance: Copyright material removed from digital thesis. See print copy in University of Adelaide Library for full text.
This electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at: http://www.adelaide.edu.au/legals
DOI: 10.4225/55/595c401158155
Appears in Collections:Research Theses

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