Prof Kevin Ryan & Dr Tom Bird
Macroautophagy (more often referred to as autophagy) is a membrane trafficking process that traffics cellular constituents to lysosomes for degradation. Due to the removal of damaged cellular constituents, the process, which is conserved from yeast to human, significantly contributes to cellular homeostasis and integrity. Autophagy therefore contributes to the prevention of human diseases including cancer. However, in the context of cancer, autophagy has also been shown to be important in promoting survival of established tumours and is therefore oncogenic.
We have evidence that cells navigate these different aspects of autophagy during tumour development via the temporal regulation of an essential autophagy regulator. In addition, we consider that the regulation of this gene may be critically important for the development of hepatocellular carcinoma.
1) To understand the detailed regulation of this gene at the molecular level in different stages of cancer.
2) To ascertain the importance of the regulation of this gene to the aetiology of hepatocellular carcinoma.
Molecular and cell biology techniques to understand the promoter regulation of this key autophagy gene. Bioinformatic studies to interrogate this gene's promoter. CRISPRi and CRISPRa screens to search for factors that control the expression of this gene in cancer. Utilization of mouse models of hepatocellular carcinoma to test the importanca of this gene in the progression of this cancer by deleting or over-expressing this gene at different stages of hepatocellular carcinoma development.
The preservation of cellular homeostasis is fundamental in protecting us against various forms of disease. One process central to the maintenance of homeostasis is macroautophagy (often referred to more simply as autophagy). This processes, which literally means ‘self-eating’, traffics cytoplasmic material to lysosomes for degradation. This results in the removal of damaged proteins and organelles. The constituent parts resulting from this breakdown are either further catabolized to make energy or recycled into biosynthetic pathways. In the context of cancer, autophagy is a major mechanism of tumour suppression as damaged cells are more prone to tumour development. In addition, however, many studies have shown that cells in established tumours are also dependent on autophagy for their survival by mitigating various forms of cellular stress. This therefore raises an apparent paradox where developing tumours must overcome the tumour suppressive effects of autophagy and then reinstate autophagy for the survival of the established tumour. In this regard, we have recently found that an essential autophagy gene may be temporally regulated to explain this collective observations. In this project the student will use molecular cell biology, bioinformatics and genetic techniques to understand the regulation to this gene in cancer progression. The results will also be validated and further explored in models of hepatocellular carcinoma, a cancer type where autophagy is heavily implicated and that is currently undergoing a rapid increase in incidence due, in part, to lifestyle choices that lead to inflammation and damage in the liver.
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Rosenfeldt, M.T., O'Prey, J., Morton, J.P., Nixon, C., MacKay, G., Mrowinska, A., Au, A., Rai, T.S., Zheng, L.,Ridgway, R., Adams, P.D., Anderson, K.I., Gottlieb, E., Sansom O.J. and Ryan, K.M. (2013) p53 determines the role of autophagy in cancer. Nature 504(7479):296-300
Sakamaki J-I., Wilkinson S., Hahn M., Tasdemir N., O'Prey J., Clark W., Hedley A., Nixon C., Long J.S., New M., Van Acker T., Tooze S.A., Lowe S.W., Dikic I. and Ryan K.M. (2017) Bromodomain Protein BRD4 Is a Transcriptional Repressor of Autophagy and Lysosomal Function. Mol. Cell 66(4):517-532
Barthet, V.J.A., Brucoli, M., Ladds, M.J.G.W., Nössing, C., Kiourtis, C., Baudot, A.D., O’Prey, J., Zunino, B., Müller, M., May, S., Nixon, C., Long, J.S., Bird T.G. and Ryan K.M. (2021) Autophagy suppresses the formation of hepatocyte-derived cancer-initiating ductular progenitor cells in the liver. Science Advances 4(7):eabf9141.
Bird TG, Müller M, Boulter L, Vincent DF, Ridgway RA, Lopez-Guadamillas E, Lu WY, Jamieson T, Govaere O, Campbell AD, Ferreira-Gonzalez S, Cole AM, Hay T, Simpson KJ, Clark W, Hedley A, Clarke M, Gentaz P, Nixon C, Bryce S, Kiourtis C, Sprangers J, Nibbs RJB, Van Rooijen N, Bartholin L, McGreal SR, Apte U, Barry ST, Iredale JP, Clarke AR, Serrano M, Roskams TA, Sansom OJ, Forbes SJ. (2018) TGFβ inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence. Sci Transl Med.10(454):eaan1230.
Kiourtis C, Wilczynska A, Nixon C, Clark W, May S, Bird TG. (2021) Specificity and off-target effects of AAV8-TBG viral vectors for the manipulation of hepatocellular gene expression in mice. Biol Open. 10(9):bio058678