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Understanding the mechanisms of metabolic reprogramming in cancer: towards novel therapies

As you read this, millions of the cells in your body are dying. Do not panic – this is not bad news. Most of them are either superfluous or potentially harmful, so you are better off without them. In fact, your health depends on the astute use of a certain kind of programmed cell death, also known as apoptosis. However, this is bad news when it comes to treatment for human cancers with anti-cancer (chemo) drugs. For reasons yet not clear certain cancer cells are resistant to death (apoptosis) induced by some chemo drugs. What’s more, is that certain cancer types are also more addicted to glucose (sugar) for the maintenance of their survival.

More specifically, cancer cells possess a near-universal metabolic phenotype known as aerobic glycolysis (or the Warburg effect), which is characterised by the consumption of glucose to generate intermediary metabolites (precursors of nucleotides, proteins and lipids) and reducing equivalents (such as NADPH) required for the doubling of cellular biomass and to suppress apoptosis, respectively. Importantly, increased aerobic glycolysis provides cancer cells with an antioxidant defense against oxidative damage induced by certain anti-cancer drugs. Therefore, studies aimed at reducing the sugar addiction of cancer cells would be beneficial for developing new treatments.

Our group, in collaboration with Dr Salvatore Papa at University of Leeds, has conducted a series of interdisciplinary studies (Barbarulo et al., Oncogene 2013; Iansante et al., Nature Commun 2015; Lee et al., Front Cell Dev Biol. 2018; Lepore et al. Hepatology 2021) to investigate the intracellular mechanisms regulating cancer cell survival.

In this project, we will examine whether drug-resistant and drug-sensitive cancer cells display distinct metabolic features and aim to do a series of laboratory experiments to investigate the ability of probes, or drugs, to starve cancer cells of glucose. If successful, this could lead to exploring the combination of drugs being tested in cancer patients.

References

• Lepore A, Choy PM, Lee NCW, Carella MA, Favicchio R, Briones-Orta MA, Glaser SS, Alpini G, D'Santos C, Tooze RM, Lorger M, Syn WK, Papakyriakou A, Giamas G, Bubici C*, Papa S. Phosphorylation and Stabilization of PIN1 by JNK Promote Intrahepatic Cholangiocarcinoma Growth. Hepatology. 2021 Nov;74(5):2561-2579

• Papa S, Choy PM and Bubici C. The ERK and JNK pathways in the regulation of metabolic reprogramming. Oncogene, 38:2223–2240 (2019).• Lee NCW, Carella MA, Papa S, Bubici C. High Expression of Glycolytic Genes in Cirrhosis Correlates With the Risk of Developing Liver Cancer. Front. Cell Dev. Biol. 6:138. (2018).

• Iansante V, Choy PM, Fung SW, Liu Y, Chai J-G, Dyson J, Del Rio A., D’Santos C, Williams R, Chokshi S, Anders RA, Bubici C and Papa S. PARP14 promotes the Warburg effect in hepatocellular carcinoma by inhibiting JNK1-dependent PKM2 phosphorylation and activation. Nat Commun, 6: 7882 (2015).

How to apply

If you are interested in applying for the above PhD topic please follow the steps below:

1. Contact the supervisor by email or phone to discuss your interest and find out if you would be suitable. Supervisor details can be found on this topic page. The supervisor will guide you in developing the topic-specific research proposal, which will form part of your application.
2. Click on the 'Apply here' button on this page and you will be taken to the relevant PhD course page, where you can apply using an online application.
3. Complete the online application indicating your selected supervisor and include the research proposal for the topic you have selected.

Good luck!

This is a self funded topic

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