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Title: Investigation of epigenetic regulators important for tumour initiation and maintenance
Author: Monserrat Sanchez, Josep
ISNI:       0000 0004 8500 0375
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2019
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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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available