LIMR Cancer: Metabolic vulnerabilities in cancer: starving tumors of essential nutrients to promote cell death

This project is available immediately to both Home-rated applicants and International applicants who 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. Applicants with sufficient funding must still undergo formal interview prior to acceptance in order to demonstrate scientific aptitude and English language capability.

<h5>Research Project</h5> <p>Every day, billions of cells in our bodies are programmed to die and be replaced by new, healthy cells. This natural process helps keep our tissues healthy and functioning properly. However, cancer cells find ways to avoid this fate. Instead of dying when damaged, they rewire their metabolism to survive, grow, and resist treatment.</p> <p>This exciting PhD project will investigate how cancer cells alter their metabolism to escape programmed cell death and continue growing. Understanding these mechanisms could reveal new ways to treat cancer by targeting the pathways that help tumour cells survive.</p> <p>Our group, in collaboration with Dr Concetta Bubici at Brunel University of London, has conducted a series of interdisciplinary studies (Barbarulo et al., <strong>Oncogene</strong> 2013; Iansante et al., <strong>Nature Commun</strong> 2015; Lee et al., <strong>Front Cell Dev Biol</strong>. 2018; Lepore et al , <strong>Hepatology</strong> 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 in-vivo models of disease. Working within an established, internationally collaborative research team, you will explore how specific genes control cell survival and metabolism in a range of cancers, including <strong>liver cancer, breast cancer, lymphoma, and myeloma</strong>. Using a combination of <strong>cell biology, mouse genetics, and metabolic analyses</strong>, you will study how these pathways influence cancer development, treatment resistance, and tissue regeneration.</p> <p>This project offers the opportunity to contribute to research with real clinical relevance and the potential to identify new therapeutic strategies for cancer patients.</p> <h5>What you will gain</h5> <p>As part of this PhD project, you will receive hands-on training in a diverse portfolio of advanced molecular and cellular biology techniques, equipping you with highly sought-after research skills for both academia and industry.<br /> You will gain expertise in powerful <strong>gene-silencing technologies</strong>, including <strong>short-hairpin RNA (shRNA)</strong> approaches and <strong>lentiviral-mediated gene knockdown</strong>, alongside state-of-the-art <strong>metabolomic analyses</strong> supported by computational interrogation of large-scale biological datasets. Training will also encompass a wide range of core and advanced laboratory techniques, including <strong>protein immunoblotting (Western blotting), immunoprecipitation and kinase assays, co-immunoprecipitation, protein pulldown analyses, PCR, gel electrophoresis, ELISA, flow cytometry, drug toxicity testing, immunohistochemistry, genotyping, </strong>and <strong>in vivo drug delivery and analysis.</strong><br /> All methodologies are fully established within the laboratory, providing an exceptional environment for developing technical expertise, generating high-quality research data, and building a strong foundation for a successful scientific career. This is a unique opportunity to work at the forefront of biomedical research while receiving comprehensive mentorship and training in both experimental and data-driven approaches.</p> <h5>References</h5> <ul> <li>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. <strong>Methods Mol Biol</strong>. 2675: 285-296 (2023).</li> <li>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, <strong>Papa S</strong>. Phosphorylation and Stabilization of PIN1 by JNK Promote Intrahepatic Cholangiocarcinoma Growth. <strong>Hepatology</strong>. 74:2561-2579 (2021)</li> <li>Lee NCW, Carella MA, Papa S, Bubici C. High Expression of Glycolytic Genes in Cirrhosis Correlates With the Risk of Developing Liver Cancer. <strong>Front. Cell Dev</strong>. <strong>Biol</strong>. 6:138. (2018).</li> <li>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. <strong>Cancer Res</strong>. 78: 1275-1292 (2018).</li> <li>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. <strong>Nat Commun</strong>, 6: 7882 (2015).</li> <li>Bubici C and Papa S. JNK signalling in cancer: in need of new, smarter therapeutic targets. <strong>Br J Pharmacol</strong>, 171: 24-37 (2014).</li> <li>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. <strong>Oncogene</strong>, 32: 4231-4242 (2013)</li> </ul> <h5>About the Institute:</h5> <p>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.</p>

<p>Please note these are not standalone projects and applicants must apply to the PhD academy directly.</p> <p>Applications can be made at any time. You should complete an <a href="https://medicinehealth.leeds.ac.uk/faculty-graduate-school/doc/apply-2">online application form</a> and attach the following documentation to support their application. </p> <ul> <li>a full academic CV</li> <li>degree certificate and transcripts of marks</li> <li>Evidence that you meet the University's minimum English language requirements (if applicable).</li> </ul> <p>To help us identify that you are applying for this project please ensure you provide the following information on your application form;</p> <ul> <li>Select PhD in Medicine, Health & Human Disease as your planned programme of study</li> <li>Give the full project title and name the supervisors listed in this advert</li> </ul> <p><em>As an international research-intensive university, we welcome students from all walks of life and from across the world. We foster an inclusive environment where all can flourish and prosper, and we are proud of our strong commitment to student education.  Within the School of Healthcare we are dedicated to diversifying our community and we welcome the unique contributions that individuals can bring, and particularly encourage applications from, but not limited to Black, Asian, people who belong to a minority ethnic community, people who identify as LGBT+; and people with disabilities. Applicants will always be selected based on merit and ability.</em></p>

You should hold a first-degree equivalent to at least a UK upper second-class honours degree in a relevant subject. A Masters degree in a relevant subject area is desirable but not essential

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 • Internet Based TOEFL - overall score of 95 with not less than 22 in listening, 22 in reading, 24 in speaking and 22 in writing.

<p>For further information about the application process, please contact the FMH PGR Admissions Team<br /> e: <a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a> </p> <p>Informal enquiries about this project can be sent directly to Dr Salvatore Papa at <a href="mailto:s.papa@leeds.ac.uk">s.papa@leeds.ac.uk</a> or Dr Concetta Bubici at <a href="mailto:concetta.bubici@brunel.ac.uk">concetta.bubici@brunel.ac.uk</a></p> <p>Laboratory website: <a href="https://papa-lab.wixsite.com/papalab">https://papa-lab.wixsite.com/papalab</a><br /> Personal website: <a href="https://medicinehealth.leeds.ac.uk/medicine/staff/668/dr-salvatore-papa">https://medicinehealth.leeds.ac.uk/medicine/staff/668/dr-salvatore-papa</a></p>