LIMR Cancer: Inhibiting cell metabolism to enhance tumour cell death

Summary

All the cells in our bodies are programmed to die. As they get older, our cells accumulate toxic molecules that make them sick. In response, they eventually break down and die, clearing the way for new, healthy cells to grow. This “programmed cell death” is a natural and essential part of our wellbeing. Every day, billions of cells die like this in order for the whole organism to continue functioning as it is supposed to.

But as with any programme, errors can occur and injured cells that are supposed to die continue to grow and divide. These damaged cells can eventually become malignant and generate tumours. In order to avoid the regular check of programmed cell death, cancer cells reprogram their metabolism so they can cheat death in order to proliferate indefinitely or resist treatment.

Cancer researchers have known for decades that tumours use a faster metabolism compared to normal cells in our body. One classic example of this is that cancer cells increase their consumption of glucose to fuel their rapid growth and strike against programmed cell death.

This means that metabolic reprogramming is pivotal to sustain cancer initiation, growth and progression. As such limiting glucose consumption in cancer cells is becoming an attractive tool for cancer treatments. However, not all cancer cell types are sensitive to the removal of glucose, and even for the cancers that are sensitive, limitation of glucose only slows down the rate of cancer progression. Therefore, the identification of intracellular pathways that regulate metabolic reprogramming of cancer cells is of great interest for possible therapeutic applications.

Our group, in collaboration with Dr Concetta Bubici at Brunel University London, 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) to investigate the intracellular mechanisms regulating cell survival (as opposed to apoptosis, a type of programmed cell death). In this project, we will investigate the intracellular pathways regulating the metabolic reprogramming in normal and disease conditions using cell-based techniques and mouse genetics. We will use in-vivo and ex-vivo experimental techniques to study cellular metabolism to understand the functional role of specific genes involved in the regulation of apoptosis in cancer chemoresistance in solid (liver and breast) and haematological (lymphoma and myeloma) cancers, as well as during tissue regeneration and tumour development.

You will gain experience in a broad range of molecular and cell biology techniques including: the powerful ‘gene silencing’ protocols using short-hairpin RNA approaches, lentivirus-mediated shRNA; immunoblotting, immunoprecipitation-complex-based kinase assay, co-immunoprecipitation and pulldown analyses, PCR, gel electrophoresis, ELISA, flow cytometry, drug-testing toxicity, immunohistochemistry, genotyping and in-vivo drug delivery and analyses. All techniques are well established within the laboratory.

References:

1. 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).

2. Verzella D, Bennett J, Fischietti M, Thotakura AK, Recordati C, Pasqualini F, Capece D, Vecchiotti D, D'Andrea D, Di Francesco B, De Maglie M, Begalli F, Tornatore L, Papa S, et al. GADD45β loss ablates innate immunosuppression in cancer. Cancer Res. 78:1275-1292 (2018).

3. Lansante 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).

This project is part of the International PhD Academy:Medical Research

In line with the bespoke nature of our International PhD Academy a modified PhD project can be proposed dependent on students interests and background.

A degree in biological sciences, dentistry, medicine, midwifery, nursing, psychology or a good honours degree in a subject relevant to the research topic. A Masters degree in a relevant subject may also be required in some areas of the Faculty. For entry requirements for all other research degrees we offer, please contact us.

Applicants whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The minimum requirements for this programme in IELTS and TOEFL tests are: • British Council IELTS - score of 7.0 overall, with no element less than 6.5 • TOEFL iBT - overall score of 100 with the listening and reading element no less than 22, writing element no less than 23 and the speaking element no less than 24.