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Title: Role for autophagy in oncogenic cell signalling and glioblastoma multiforme
Author: Fraser, Jane Elizabeth
ISNI:       0000 0004 7969 1608
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2019
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The catabolic process of macroautophagy occurs constitutively in eukaryotic cells at a basal level and can become upregulated during periods of stress to recycle nutrients and promote cell survival. The role of this process in disease states is starting to be explored, particularly in cancers where the rapid growth and proliferation of cells generates a stressful environment. During the course of this study I investigated the role of autophagy in the aggressive brain cancer glioblastoma multiforme (GBM), focussing on the regulation of cellular signalling pathways that are known to drive oncogenesis. Specifically, I find that autophagy is required for tumour formation in an in vivo KRasG12D-driven mouse model of GBM, correlating in vitro with the suppression of senescence and stimulation of pro-growth signalling pathways. Additionally, autophagy is seen to promote anchorage-independent growth in a panel of cell line models of GBM, as well as being required for maintenance of cell signalling activities upon anchorage loss. Further exploration of cellular signalling activities revealed that the knockout of autophagy gene expression significantly reduces ligand-induced signalling from receptor tyrosine kinases, such as the epidermal growth factor receptor (EGFR), which is frequently mutated in GBM. The endocytic trafficking of EGFR is found to be perturbed in autophagy-deficient cells, with the receptor accumulating in early endosomes rather than maturing into recycling endosomes and returning back to the plasma membrane for renewed activation. Mechanistically, autophagy players localise to endosomal structures, which appear morphologically disrupted upon loss of autophagy gene expression, thereby suggesting that autophagy may directly regulate endosomal homeostasis. Together, these results support a role for autophagy in facilitating the oncogenic cell signalling that drives GBM.
Supervisor: Gammoh, Noor ; Pollard, Steven Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: glioblastoma multiforme ; autophagy ; tumourigenic signals ; oncogenic cell signalling