Monserrat Sanchez, Josep;
(2019)
Investigation of epigenetic regulators important for tumour initiation and maintenance.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Epigenetic deregulation is a widespread phenomenon of human cancer that leads to the acquisition and maintenance of malignant cellular behaviours. However, our understanding of the precise molecular mechanisms underlying these abnormal properties, as well as whether epigenetic regulators play distinct roles in the initiation and in the later stages of the disease remain largely elusive. // Using a model system of human cancer development that grants temporal control over malignant cellular transformation, I initially performed two loss-of-function CRISPR-Cas9 screens to dissect the basis of epigenetic dysregulation in tumorigenesis and in tumour maintenance. Through a combination of functional and computational approaches, I subsequently confirmed the screen results and obtained important insights into the pathological role of epigenetic regulators at distinct disease stages. Firstly, I show that epigenetic regulators act as a tumour suppressive barrier to prevent acquisition of tumour-initiating ability in oncogenic-challenged cells. Moreover, using in vivo mouse models of lung cancer development and analysing cancer patient datasets, I reveal that alterations in the protein levels of multiple epigenetic regulators have profound implications in the efficiency of malignant transformation. Secondly, I identified that cancer cells from numerous patient derived samples depend on the MSL acetyltransferase complex to sustain long-term tumour growth. Mechanistically, I find that loss of uncontrolled proliferative potential in MSL-deficient cells is due to an increase in chromosomal instability and adoption of unviable aneuploid states beyond the threshold tolerated by cancer cells. // Therefore, by interrogating the role of epigenetic regulators at distinct points in the disease, I unveil novel cellular and molecular insights into their pathological role.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Investigation of epigenetic regulators important for tumour initiation and maintenance |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10079704 |
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