Cancer Sciences PhD/iPhD/MD/MSc (Research)

Supervisors: Dr Stephen McSorley and Dr Johan Vande Voorde 

Project description: Around 40% of individuals undergoing bowel screening colonoscopy have pre-malignant colorectal adenomas. Despite excising them patients remain at increased risk of further adenomas and colorectal cancer (CRC) in the future with no means of prevention available other than repeated colonoscopies.

Immune responses and infiltrates of specific subtypes of immune cells called T lymphocytes within adenomas are associated with a patient’s likelihood of future adenomas and CRC. It is unclear what drives differences in these immune responses to adenomas in the colon and ultimately outcomes.

The colonic microbiome – the variety and location of different species of bacteria, fungi and viruses within the large bowel - has been implicated in colorectal carcinogenesis including the formation of new adenomas and progression of adenomas to cancer. Furthermore, in established CRC, interaction between the microbiome and immune system is thought to impact outcomes.
This exciting PhD project will build on an existing highly annotated dataset of around 2600 patients who have undergone surveillance following polypectomy at bowel screening colonoscopy with matched tissue. The student will be involved in the prospective collection of colonic tissue and samples from patients having adenomas removed at colonoscopy. They will interrogate immune – microbiome interactions within adenoma and surrounding colonic biopsy tissue using techniques including immunohistochemistry, RNAseq, RNAscope, and state of the art spatial proteomic/transcriptomic technologies – Nanostring, GeoMx, DSP, and CosMx SMI.

The identification of specific immune system and microbiome targets associated with future adenoma risk will eventually permit drug screening and chemoprevention in a large group of high-risk patients for whom repeated colonoscopy is the only current management option.

Fees: There are no funds available for this PGR project. Applicants must have sufficient funds to pay for their support and PGR fees.

To apply, please contact supervisors and include project title in application. 

Supervisors: Xiao Fu, John Le Quesne

MSc choice: Cancer Research & Precision Oncology [MSc]

Project description: Tumour microenvironments (TMEs) profoundly influence cancer progression and shape the response to anti-cancer therapy. Recent advances in digital pathology and innovative data analytics including machine learning have enhanced our ability to identify clinically relevant spatial characteristics of TMEs [1]. In lung cancer, several deep learning studies using Haematoxylin and Eosin (H&E) images have demonstrated that the spatial organisation of stromal and immune cell populations within the TME are relevant to tumour evolution and patient survival outcomes [2-4].

This PhD project will seek to investigate the prognostic value of spatial immunophenotypes in lung cancer combining high-plex imaging, spatial data analysis, and machine learning. One arm of the project will seek to engineer diverse quantitative features (e.g., adapting concepts and metrics from network science [5] to characterise cellular graphs) of the spatial immunophenotypes that are mapped in high-plex immunofluorescence images and evaluate their prognostic values in lung cancer. The other arm of the project will seek to develop deep learning models (e.g., adapting methods in [6]) based on spatial cellular graphs constructed from these images to predict clinical outcomes.

The research will be carried out using two comprehensively annotated cohorts of non-small-cell lung cancer patients, including LATTICe-A cohort (Leicester Archival Thoracic Tumour Investigatory Cohort- Adenocarcinoma), which comprises 1000 resected primary lung adenocarcinomas, and the Glasgow early non-small cell lung cancer cohort, which will comprise 1000 cases (including squamous cell carcinoma and other non-small cell varieties of lung cancer) upon completion next year. Several high-plex imaging methods (e.g., Vectra Polaris, PhenoCycler) will be applied to map spatial immunophenotypes, which are in addition to abundant genomic and RNA sequencing data as well as H&E images of the same tumours.
This project will be jointly supervised by Xiao Fu and John Le Quesne. The student will have an exciting opportunity to receive training in state-of-the-art imaging techniques, quantitative data analysis, and machine learning. The successful candidate will join the dynamic and collaborative research environment of the CRUK Beatson Institute, working with a diverse multidisciplinary team of computer scientists, bioinformaticians, clinicians, and experimental scientists.

References

1. Fu X, Sahai E, Wilkins A. Application of digital pathology-based advanced analytics of tumour microenvironment organisation to predict prognosis and therapeutic response. J Pathol. 2023;260(5):578-591. doi:10.1002/path.6153
2. AbdulJabbar K, Raza SEA, Rosenthal R, et al. Geospatial immune variability illuminates differential evolution of lung adenocarcinoma. Nat Med. 2020;26(7):1054-1062. doi:10.1038/s41591-020-0900-x
3. Zhang H, AbdulJabbar K, Moore DA, et al. Spatial Positioning of Immune Hotspots Reflects the Interplay between B and T Cells in Lung Squamous Cell Carcinoma. Cancer Res. 2023;83(9):1410-1425. doi:10.1158/0008-5472.CAN-22-2589
4. Quiros AC, Coudray N, Yeaton A, et al. Mapping the landscape of histomorphological cancer phenotypes using self-supervised learning on unlabeled, unannotated pathology slides. arXiv. 2023
5. Albert-László Barabási. Network Science. Cambridge University Press. 2016. http://networksciencebook.com/
6. Wu Z, Trevino AE, Wu E, et al. Graph deep learning for the characterization of tumour microenvironments from spatial protein profiles in tissue specimens. Nat Biomed Eng. 2022;6(12):1435-1448. doi:10.1038/s41551-022-00951-w

Supervisors: Vignir Helgason, Eric Kalkman

MSc choice: Cancer Research & Precision Oncology [MSc]

Our lab is interested in biological processes that contribute to drug resistance in myeloid leukaemias, with particular focus on leukaemic stem cells (LSCs).

Introduction: Chronic myeloid leukaemia (CML) is caused by a reciprocal chromosomal translocation within a haemopoietic stem cell. This leads to transcription of BCR-ABL, a constitutively active tyrosine kinase that is necessary to induce CML.

The development of the tyrosine kinase inhibitor (TKI) significantly improved the life expectancy of CML patients; however, we have shown that disease persistence is caused by the remarkable ability of CML LSCs to survive, despite complete BCR-ABL inhibition mediated by TKI treatment1,2. Acute myeloid leukaemia (AML) is a more heterogeneous, involving different disease-causing genetic mutations. First line treatment for AML patients consists of chemotherapy, aiming at inducing remission. Generally, five-year survival rate in AML remains at a dismal 20%.

Activating internal tandem duplication mutations in FLT3 (FLT3-ITD), detected in about 20% of AML, represents driver mutations and a valid therapeutic target in AMLFLT-ITD. However, although new FLT3 inhibitors have begun to show promising clinical activity it is unlikely that they will have durable effects as single agents In recent years there has been resurgence in interest in autophagy, energy metabolism and mitochondria function as a possible area for development of novel anti-cancer agents.

We recently developed improved protocols for autophagy and metabolic assays in rare LSCs and highlighted mitochondrial oxidative phosphorylation (OXPHOS) as a metabolic dependency in CML LSCs3. Primitive AML cells have also been shown to depend on increased mitochondrial respiration4,5. We will therefore further investigate mitochondrial metabolism and through validation of drug-repurposing screen, identify new clinically applicable drugs that inhibit OXPHOS in CML, and in AML where improved therapy options with acceptable toxicities are urgently needed.

Hypothesis/aims: Our working hypothesis is that autophagy and deregulated mitochondrial metabolism in LSCs renders them sensitive to inhibition of the ULK1 autophagy complex and pathways that sustain mitochondrial OXPHOS. Our first aim is to use complementary functional and omic approaches to further assess the dependency of CML/AML LSCs to recycle or oxidise major mitochondrial fuels (objective 1). Our second aim is to test ULK1 inhibitors6 and FDA-approved OXPHOS inhibitors (which we have recently identified through drug-repurposing screening), in combination with TKI treatment, for eradication of CML and AMLFLT3-ITD/TKD LSCs (objective 2).

Deliverables: This project will therefore promote identification of a core fuel pathway signature of CML/AML LSCs and a set of new potentially selective LSC-specific metabolic drug targets (objective 1). The student will also use state-of-the-art in vitro and in vivo models to test clinically relevant drugs, which will in the longer term, facilitate the translation of our findings into the clinic, with the overall aim for CML and AML LSC eradication.

References

1. Holyoake, T.L., et al. Immunological reviews. 106-23 (2015).
2. Hamilton, A., et al. Blood. 1501-10 (2012).
3. Kuntz, E.M., et al. Nat Med. 1234-40 (2017).
4. Skrtic, M., et al. Cancer Cell. 674-88 (2011).
5. Lagadinou, E.D., et al. Cell Stem Cell. 329-41 (2013).
6. Ianniciello, A., et al. Sci Transl Med. (2021)

Supervisor: Dr. Joanna B. Wilson

MSc choice: Cancer Research & Precision Oncology [MSc]

Background: Epstein-Barr virus (EBV) is a human Herpesvirus that is associated with several forms of human cancer. The virus leads to a life long infection, avoiding eradication by the immune system and has evolved intriguing tricks to do this. In the lab we investigate the role of key viral genes in disease processes, their mechanism of action at the molecular level and how they perturbate the immune system. Central to this are the mechanisms by which viral proteins disrupt normal cellular processes. New insights into viral action permit an exploration into novel therapeutic approaches to combat EBV-associated cancer.

Aims: To assess the efficiency of novel treatments in killing viral infected tumour cells and to explore the mechanism of action of such drugs in targeting the function of selected viral proteins

Techniques: The project will involve the use of several molecular biological and genetical techniques to examine protein, DNA, RNA and molecular interactions, as well as immunological and cell culture methods, also high resolution imaging.

References

1. AlQarni, S., Al-Sheikh, Y., Campbell, D., Drotar, M., Hannigan, A., Boyle, S., Herzyk, P., Kossenkov, A., Armfield, K., Jamieson, L., Bailo, M., Lieberman, P., Tsimbouri, P. and Wilson, J.B. (2018) Lymphomas driven by Epstein-Barr virus nuclear antigen-1 (EBNA1) are dependant upon Mdm2. Oncogene (in the press)
2. Gnanasundram, S.V., Pyndiah, S., Daskalogianni, C., Armfield, K., Nylander, K. , Wilson, J.B. and Fåhraeus,, R. (2017) PI3Kd activates E2F1 synthesis in response to EBNA1-induced mRNA translation stress. Nature Communications 8:2103, doi:10.1038/s41467-017-02282-w Gao, X., Lampraki, E., Al-Khalidi, S., Qureshi, M.A., Desai, R. and Wilson, J.B. (2017) N-acetyl cysteine (NAC) ameliorates Epstein-Barr virus latent membrane protein 1 induced chronic inflammation. PLoS-ONE 12 (12) e0189167
3. Deschamps, T., Quentin, B, Leske, D.M., MacLeod, R., Mompelat, D., Tafforeau, L., Lotteau, V., Baillie, G.S., Gruffat, H., Wilson, J.B. and Manet, E. (2017) Epstein-Barr Virus Nuclear Antigen 1 (EBNA1) interacts with Regulator of Chromosome Condensation (RCC1) dynamically throughout the cell cycle. J. Gen. Virol. 98:251-265 PMID:28284242
4. Hussain, M., Gatherer, D. and Wilson, J.B. (2014) Modelling the structure of full-length Epstein-Barr Virus Nuclear Antigen 1. Virus Genes 49:358-372 PMID: 25011696

Supervisors: David Bryant, Owen Sansom

MSc choices: Cancer Research & Precision Oncology [MSc] 

Summary: The majority of cancer-related deaths are associated with metastasis from the primary tumour. Cancer metastasis treatment is therefore a major unmet need in the clinic. The sialomucin Podocalyxin is a potential biomarker and molecular regulator of metastasis across a number of tumour types.

In this PhD project, the candidate will utilise a combination of cutting-edge mouse models of metastatic colorectal cancer and mini-tumour avatars in the laboratory to understand how Podocalyxin drives metastasis. This will include identification of those colorectal tumours in which Podocalyxin levels can be a biomarker to indicate which patients will have metastases, and whether function-blocking antibodies can be an effective treatment in vivo to avert metastasis. The candidate will receive outstanding training in mouse models of cancer, genetic editing and molecular analysis of cancer cells, 3-Dimensional culture techniques, and advanced live imaging and analysis. The PhD project is aimed at improving our understanding of the mechanisms of metastasis and identifying potential molecularly targeted therapies.

References

1. Román-Fernández A, Mansour MA, Kugeratski FG, Anand J, Sandilands E, Galbraith L, Rakovic K, Freckmann EC, Cumming EM, Park J, Nikolatou K, Lilla S, Shaw R, Strachan D, Mason S, Patel R, McGarry L, Katoch A, Campbell KJ, Nixon C, Miller CJ, Leung HY, Le Quesne J, Norman JC, Zanivan S, Blyth K, Bryant DM. Spatial regulation of the glycocalyx component podocalyxin is a switch for prometastatic function. Sci Adv. 2023 Feb 3;9(5):eabq1858. doi: 10.1126/sciadv.abq1858. Epub 2023 Feb 3. PubMed PMID: 36735782; PubMed Central PMCID: PMC9897673.
2. Jackstadt R, van Hooff SR, Leach JD, Cortes-Lavaud X, Lohuis JO, Ridgway RA, Wouters VM, Roper J, Kendall TJ, Roxburgh CS, Horgan PG, Nixon C, Nourse C, Gunzer M, Clark W, Hedley A, Yilmaz OH, Rashid M, Bailey P, Biankin AV, Campbell AD, Adams DJ, Barry ST, Steele CW, Medema JP, Sansom OJ. Epithelial NOTCH Signaling Rewires the Tumor Microenvironment of Colorectal Cancer to Drive Poor-Prognosis Subtypes and Metastasis. Cancer Cell. 2019 Sep 16;36(3):319-336.e7. doi: 10.1016/j.ccell.2019.08.003. PMID: 31526760; PMCID: PMC6853173.

Supervisor: Dr Karen Keeshan

MSc choice: Cancer Research & Precision Oncology [MSc]

Abstract: Acute myeloid leukaemia (AML) is a genetically and phenotypically heterogeneous disease that is characterized by a block in myeloid differentiation, as well as enhanced proliferation and survival. It affects people of all ages with an incidence of 2-3 per 100 000 per annum in children, increasing to 15 per 100 000 per annum in older adults. The relapse risk for childhood AML remains unacceptably high and relapse is the commonest cause of death. Multiple courses of chemotherapy remain the mainstay of treatment in adult and childhood AML but a ceiling of benefit has been reached and toxicity is significant (Chaudhury et al, 2015). There have been few, if any, new treatments in the past 30 years and there is a pressing need for novel effective therapies in AML.

The treatment of paediatric AML is in essence extrapolated from that of adults with AML. Our previous work (Chaudhury et al, 2018) have questioned the appropriateness of this approach which assumes that a similar aetiology underlies AML in the young and old, . providing evidence that disease characteristics differ between a paediatric and adult population with AML Functional interplay between AML cells and the bone marrow microenvironment is a distinctive characteristic of AML disease. AML cells in the adult bone marrow BM reside in leukaemic niches (Aung et al. 2020) that support leukaemic cell survival and expansion. The importance of the microenvironment in paediatric versus adult AML (fetal liver, cord blood, bone marrow) and its role is disease characteristics has not been well explored. Our lab focuses on the proliferation and self-renewal capabilities of the leukaemic cell and the influence of the leukaemic niche including mesenchymal stem cells. We hypothesize that the microenvironment influences the initiation, maintenance, and aggressiveness of paediatric and adult AML disease.

Methods & approaches: This project will investigate the role of the microenvironment in AML disease initiation and maintenance,. particularly the crosstalk between mesenchymal stem cells and AML cells and how it impacts disease chemoresistance and relapse.

We will focus on genetically distinct subtypes of paediatric and adult using a number of models and approaches including: Bone marrow transduction and transplantation (BMT) murine models: expression of AML oncogenes in viral constructs and using CRISPR/Cas9 gene editing approaches; assessments on disease in vivo; Stromal co-cultures and transcriptional profiling using single cell RNA-sequencing; primary AML samples from paediatric and adult patients. The project will also employ flow cytometry, cellular and molecular biology technologies. This PhD studentship offers extensive dual training in both fundamental and translational biology of leukaemia, an environment encompassing clinical and basic researchers, and training opportunities as part of the college graduate programme.

References

1. Chaudhury SS, Morison JK, Gibson BES, Keeshan K. Insights into cell ontogeny, age and acute myeloid leukaemia. Experimental Hematology. 2015 Jun 4.

2. Chaudhury S, O'Connor C, Canete A, Bittencourt-Silvestre J, Sarrou E, Prendergast A, Choi J, Johnston P, Wells CA, Gibson B, Keeshan K. Age-specific biological and molecular profiling distinguishes paediatric from adult acute myeloid leukaemias. Nat Commun. 2018;9(1):5280

3. Aung MMK, Mills ML, Bittencourt-Silvestre J, Keeshan K. Insights into the molecular profiles of adult and paediatric acute myeloid leukaemia. Mol Oncol. 2021;15(9):2253-72.

Supervisors: Imran Ahmad, Tom MacVicar

MSc choices: Cancer Research & Precision Oncology [MSc]

Summary: Remarkable prostate cancer cell metabolic flexibility and plasticity enables tumours to grow and combat androgen therapy. Mitochondria are essential organelles that support tumour adaptation, with changes in form and function that are dynamically reprogrammed during tumorigenesis. Previous work in our group has identified the key role of the metabolic regulator PPARG in driving metastatic prostate cancer.

In this innovative PhD project, the candidate will use 3D tumour models combined with genetically engineered mouse models to investigate how mitochondria contribute to tumorigenesis and treatment resistance. The candidate will study mitochondrial reprogramming in these models with state-of-the-art compartmentalised metabolomic and proteomic techniques. These studies will improve our basic understanding of mitochondrial reprogramming in tumours and may identify novel therapeutic targets for prostate cancer.

Reference

1. Galbraith LCA, Mui E, Nixon C, Hedley A, Strachan D, MacKay G, Sumpton D, Sansom OJ, Leung HY, Ahmad I. “PPAR-gamma induced AKT3 expression increases levels of mitochondrial biogenesis driving prostate cancer”. Oncogene 2021; doi: 10.1038/s41388-021-01707-7

Supervisors:  Stephen Tait, Ed Roberts

MSc choice: Cancer Research & Precision Oncology [MSc]

Project description: Cell death both prevents and treats cancer. New anti-cancer therapies that directly target cell death are revolutionising the treatment of cancer. Nevertheless, a major problem to effective cancer treatment is the emergence of treatment resistance. We are interested in killing cancer cells in a way that alerts the immune system to the presence of cancer - in essence harnessing the power and adaptability of tumour immunity to eradicate cancer. Our focus is on mitochondrial apoptosis - we have found that blocking caspase protease activity makes cell death immunogenic.

This PhD project will seek to understand why such caspase-inhibited cell death is immunogenic - both at the level of the dying cell but also in understanding how the immune system responds to the dying cell. We will employ novel approaches to inhibit caspase activity. In short, this exciting project will focus on discovery science with clear translation impact for cancer treatment.

The techniques it will entail will be varied but include CRISPR-Cas9 genome editing, super-resolution microscopy and in vivo modelling of cancer. This will be a collaborative project jointly supervised by Stephen Tait and Ed Roberts. You will join a young, dynamic interdisciplinary research team, based withing the CR-UK Beatson Institute with access to cutting edge technology.

References

1. Targeting immunogenic cell death in cancer. Ahmed A, Tait SWG. Mol Oncol. 2020 Dec;14(12):2994-3006. doi: 10.1002/1878-0261.12851. Epub 2020 Dec 1.
2. Mitochondrial permeabilization engages NF-κB-dependent anti-tumour activity under caspase deficiency

1. Create your own proposal - approximately 1000 words and must include:
   • a straightforward, descriptive, and informative title
   • the question that your research will address
   • an account of why this question is important and worth investigating
   • an assessment of how your own research will engage with recent research in the field
   • a brief account of the methodology and approach you will take.
2. You will need to contact a supervisor prior to application, using the search function.

Supervisor Search

Based on your proposal, your supervisor will choose an MSc programme that aligns with your research interests.