Metabolic reprogramming in cancer: starving tumors of essential nutrients to promote cell death

PGR-P-2226

Key facts

Type of research degree: PhD
Application deadline: Ongoing deadline
Country eligibility: International (open to all nationalities, including the UK)
Funding: Non-funded
Supervisors: Dr Salvatore Papa
Schools: School of Healthcare, School of Medicine

<h2 class="heading hide-accessible">Summary</h2>

This project is available immediately to both Home/EU rate applicants and International applicants who are have a sponsor or are able to self-fund their studies. Students must be able to provide the appropriate level of fees based on their fee status plus laboratory consumables costs per year. This is in addition to the provision of personal living expenses. You should hold a first degree equivalent to at least a UK upper second class honours degree in a relevant subject. Candidate whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study, the Faculty minimum requirements are: • British Council IELTS - score of 6.5 overall, with no element less than 6.0 • TOEFL iBT - overall score of 92 with the listening and reading element no less than 21, writing element no less than 22 and the speaking element no less than 23. Applicants with sufficient funding must still undergo formal interview prior to acceptance in order to demonstrate scientific aptitude and English language capability.

<h2 class="heading hide-accessible">Full description</h2>

Research Project: 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 of 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; Lepore et al , Hepatology 2021) 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. About the Institute: The Leeds Institute of Medical Research (LIMR) at St. James’s is a vigorous and highly interactive research institute that investigate the causes and treatment of disease at the level of molecules, cells, patients and populations. The Institute research interests include the genetics, genomics and cell biology of disease, haematology and immunology, cancer research (from basic biology through to clinical trials and outcomes research), gastroenterology, surgery and pathology and the use and integration of big data sets into these problems. Reference: • Lepore A, Kaci FN, Bubici C, Papa S. An Integrated Methodology to Quantify the Glycolytic Stress in Plasma Cell Myeloma in Response to Cytotoxic Drugs. Methods Mol Biol. 2675: 285-296 (2023). • 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. 74:2561-2579 (2021) • 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). • 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). • 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). • Bubici C and Papa S. JNK signalling in cancer: in need of new, smarter therapeutic targets. Br J Pharmacol, 171: 24-37 (2014). • Barbarulo A, Iansante V, Chaidos A, Naresh K, Rahemtulla A, Franzoso G, Karadimitris A, Haskard DO, Papa S & Bubici C. Poly(ADP-ribose) polymerase family member 14 (PARP14) is a novel effector of the JNK2-dependent pro-survival signal in multiple myeloma. Oncogene, 32: 4231-4242 (2013).

<h2 class="heading">How to apply</h2>

Applications can be made at any time. To apply for this project applicants should list the project title: Metabolic reprogramming in cancer: starving tumors of essential nutrients to promote cell death and supervisor name: Dr Salvatore Papa while applying. We also require 2 academic references to support your application. Please ask your referees to send these <a href="http://medhealth.leeds.ac.uk/download/2377/scholarship_reference_form" rel="noreferrer noopener" target="_blank">references</a> on your behalf, directly to <a href="mailto:fmhgrad@leeds.ac.uk" rel="noreferrer noopener" target="_blank">fmhgrad@leeds.ac.uk</a> If you have already applied for other scholarships using the Faculty Scholarship Application form this academic session you do not need to complete this form again. Instead you should email <a href="mailto:fmhgrad@leeds.ac.uk" rel="noreferrer noopener" target="_blank">fmhgrad@leeds.ac.uk</a> to inform us you would like to be considered for this scholarship project. Any queries regarding the application process should be directed to <a href="mailto:fmhgrad@leeds.ac.uk" rel="noreferrer noopener" target="_blank">fmhgrad@leeds.ac.uk</a>. Informal enquiries about this project can be sent directly to Dr Salvatore Papa at <a href="mailto:s.papa@leeds.ac.uk" rel="noreferrer noopener" target="_blank">s.papa@leeds.ac.uk</a> Laboratory website: <a href="https://papa-lab.wixsite.com/papalab" rel="noreferrer noopener" target="_blank">https://papa-lab.wixsite.com/papalab</a> Personal website: <a href="https://medicinehealth.leeds.ac.uk/medicine/staff/668/dr-salvatore-papa" rel="noreferrer noopener" target="_blank">https://medicinehealth.leeds.ac.uk/medicine/staff/668/dr-salvatore-papa</a>

<h2 class="heading heading--sm">Entry requirements</h2>

Applicants to research degree programmes should normally have at least a first class or an upper second class British Bachelors Honours degree (or equivalent) in an appropriate discipline. The criteria for entry for some research degrees may be higher, for example, several faculties, also require a Masters degree. Applicants are advised to check with the relevant School prior to making an application. Applicants who are uncertain about the requirements for a particular research degree are advised to contact the School or Graduate School prior to making an application.

<h2 class="heading heading--sm">English language requirements</h2>

The minimum English language entry requirement for research postgraduate research study is an IELTS of 6.5 overall with at least 6.0 in each component (reading, writing, listening and speaking) or equivalent. The test must be dated within two years of the start date of the course in order to be valid. Some schools and faculties have a higher requirement.

<h2 class="heading">Contact details</h2>

For further information please contact the Graduate School Office e: <a href="mailto:EMAIL@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a>