Research projects

+++

Developing CRISPR tools for targeting tumour suppressors in Mesothelioma

Primary supervisor: Daniel Murphy

Project summary

oin the world-leading Mesothelioma research laboratory of Prof Daniel J. Murphy to develop new CRISPR tools to investigate the functional role of under-investigated tumour suppressor genes in Mesothelioma PMID:37441092.  We are the UK’s only laboratory routinely using state of the art in vivo models to investigate this lethal cancer and your contribution could have a meaningful impact on our work. We will help you develop the skills you need to advance your career in an exciting area of cancer research, along with the transferable skill to give you flexibility in your future direction.

Aims and overall techniques

The primary aim of this project is to develop and validate CRISPR vectors targeting additional clinically relevant TSGs. Vectors will be designed and subcloned, then tested in cell culture for their ability to accurately disrupt TSG expression. Validated vectors will subsequently be used by Murphy lab personnel in vivo to understand the contribution of each TSG to Mesothelioma development.

---

+++

An assessment of vulnerabilities in phosphoinositide signaling to attenuate metastatic colorectal cancer.

Supervisors: David Bryant, Emma Sandilands and Archana Katoch

Project summary: Mutation in the lipid phosphatidylinositol-3-kinase (PI3K) or in PTEN, the phosphatase that reverses PI3K action is frequent in human cancers. We utilise organoids derived from poor outcome colorectal cancers which are genetically engineered ex vivo, transplanted in vivo, and the effect on tumourigenesis and metastasis examined. We identified that PTEN knockout rapidly accelerates metastasis. Our current work using CRISPR in vivo is identifying which additional PI3K pathway enzymes can, conversely to PTEN loss, attenuate metastasis.

This project aims to identify the mechanism of action of PI3K pathway enzymes that attenuate colorectal cancer tumourigenesis and metastasis. The candidate will join a team of researchers utilise a combination of cutting-edge mouse models of metastatic colorectal cancer and organoids to understand how inhibiting the PI3K pathway may be a potential treatment to perturb tumourigenesis and metastasis.

The candidate will receive training in CRISPR-mediated genetic editing, molecular analysis of cancer cells, 3-Dimensional culture techniques, advanced live imaging and image analysis.

References

1. Nikolatou K, Sandilands E, Román-Fernández A, Cumming EM, Freckmann E, Lilla S, Buetow L, McGarry L, Neilson M, Shaw R, Strachan D, Miller C, Huang DT, McNeish IA, Norman JC, Zanivan S, Bryant DM. PTEN deficiency exposes a requirement for an ARF GTPase module for integrin-dependent invasion in ovarian cancer. EMBO J. 2023 Sep 18;42(18):e113987. doi: 10.15252/embj.2023113987. Epub 2023 Aug 14. PMID: 37577760; PMCID: PMC10505920.
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.
3. Nacke M, Sandilands E, Nikolatou K, Román-Fernández Á, Mason S, Patel R, Lilla S, Yelland T, Galbraith LCA, Freckmann EC, McGarry L, Morton JP, Shanks E, Leung HY, Markert E, Ismail S, Zanivan S, Blyth K, Bryant DM. An ARF GTPase module promoting invasion and metastasis through regulating phosphoinositide metabolism. Nat Commun. 2021 Mar 12;12(1):1623. doi: 10.1038/s41467-021-21847-4. PubMed PMID: 33712589; PubMed Central PMCID: PMC7955138.
4. Román-Fernández Á, Roignot J, Sandilands E, Nacke M, Mansour MA, McGarry L, Shanks E, Mostov KE, Bryant DM. The phospholipid PI(3,4)P(2) is an apical identity determinant. Nat Commun. 2018 Nov 28;9(1):5041. doi: 10.1038/s41467-018-07464-8. PubMed PMID: 30487552; PubMed Central PMCID: PMC6262019

---

+++

Assessing the activity of novel compounds in Human Derived Biliary Tract Cancer preclinical models.

Supervisors: Chiara Braconi and Sergi Marco

Project summary: Biliary Tract Cancers (BTC) are tumours arising from the bile duct within and outside the liver. There is an unmet need to develop novel therapeutic strategies that can impact on survival of BTC patients. Here we will test novel compounds in multicellular, patients’ derived, preclinical models to identify the clinical potential of these compounds and define the best strategies for designing their clinical implementation. The candidate will develop skills in cell culturing, with particular reference to 3D models, and molecular biology with the development of stably transfected clones. She/he will also have an opportunity to develop troubleshooting skills and critical thinking. There will be particular attention to the training of the presentations skills with need to present regularly at the lab meeting and possibility to present at international meetings should the candidate be considered appropriately skilled and trained.

---

+++

Circadian rhythm disruption in colorectal cancer metastasis

Supervisors: Zoi Diamantopoulou and Kendle Maslowski

Project summary: The circadian rhythm, an internal timekeeping system regulated by core clock genes, controls various physiological processes. Disruptions in this rhythm are linked to chronic diseases, including cancer. Our recent research has uncovered a connection between the circadian rhythm and breast cancer metastasis, revealing that circulating tumour cells (CTCs) are predominantly generated during the rest phase of the circadian cycle, influenced by the body’s hormonal rhythms. Building on this, the current study aims to explore the role of the circadian rhythm in colorectal cancer metastasis, by assessing whether cancer cells retain rhythmic core clock gene function. We will screen colorectal cancer cells and organoids and assess their circadian rhythm functionality, investigating potential links between clock gene expression and cancer progression. The study will also explore how genetic mutations affect circadian rhythm in colorectal cancer. The ultimate goal is to leverage circadian rhythm vulnerabilities to develop novel anti-metastatic therapies.

References:

1. Diamantopoulou Z, et al., Trends in Cell Biology. 2023 Oct 3;120(40).
2. Lawrence, R. et al., Nat Rev Clin Oncol. 2023
3. Diamantopoulou Z, et al., Nature. 2022 Jul;607(7917):156-162
4. Chun, S.K. et al. Sci. Adv. 2022
5. Stokes, K. et al. Cellular and Molecular Gastroenterology and Hepatology 2021

---

+++

Developing Computational Modelling and Systems Biology Approaches to Study Liver Regeneration and Cancer

Supervisors: Xiao Fu and Tom Bird

Project summary: Fundamental to liver’s functions, various cell types are organised into spatial zones within the hepatic lobule (liver’s architectural units), and hepatocytes maintain zonal gradients of gene expression profiles and metabolic programmes.

With recent advances of spatial phenotyping techniques, the division of labour and crosstalk between cells within the hepatic lobule are beginning to be characterised at unprecedented resolutions, in the healthy liver as well as in liver regeneration and cancer.

Leveraging publicly available spatial datasets, this project aims to develop data-informed computational modelling and systems biology framework to dissect molecular and cellular mechanisms shaping spatial and temporal trajectories of liver regeneration and cancer. Linking computer simulations with experimental observations will further uncover intrinsic and extrinsic factors shaping clonal expansion in mouse models of liver cancer.
The student will work with an interdisciplinary team of project supervisors and gain transferable computational skills as well as knowledge in liver biology.

References:

1. Fu X, Sluka JP, Clendenon SG, et al. Modeling of xenobiotic transport and metabolism in virtual hepatic lobule models. PLoS One. 2018;13(9):e0198060. Published 2018 Sep 13. doi:10.1371/journal.pone.0198060
2. Fu X, Zhao Y, Lopez JI, et al. Spatial patterns of tumour growth impact clonal diversification in a computational model and the TRACERx Renal study. Nat Ecol Evol. 2022;6(1):88-102. doi:10.1038/s41559-021-01586-x

---

+++

Exploiting mitochondrial inflammatory signals to engage anti-tumour immunity.

Supervisors: Stephen Tait and Danny Huang  

Project summary: Cell death prevents and treats cancer. Typically, therapies cause apoptotic cell death of cancer cells. In brief, apoptosis requires mitochondria to activate proteases call caspases. Apoptosis is a silent form of cell death that fails to evoke an immune response. We have found that killing cells under caspase inhibition elicits powerful anti-tumour immunity that can eradicate cancer in experimental models. Underlying this are inflammatory signals sent out by the mitochondria. This project aims to understand the fundamental mechanisms of inflammation triggered by permeabilized mitochondria. It will entail a variety of cutting-edge methods including genome-engineering, high-resolution microscopy and in vivo tumour biology. Using this knowledge our goal is to enhance our ability to effectively kill cancer by engaging anti-tumour immunity.

References

1. Mitochondrial permeabilization engages NF-κB-dependent anti-tumour activity under caspase deficiency. Giampazolias et al, Nat Cell Biol. 2017 Sep;19(9):1116-1129.doi: 10.1038/ncb3596.
2. Mitochondrial inner membrane permeabilization enables mtDNA release during apoptosis. Riley et al, EMBO J (2018)37:e99238 https://doi.org/10.15252/embj.201899238
3. Mitochondrial outer membrane integrity regulates a ubiquitin-dependent NF-κB inflammatory response. Vringer et al, doi: https://doi.org/10.1101/2023.09.21.558776
4. Apoptotic stress causes mtDNA release during senescence and drives the SASP. Victorelli et al, Nature volume 622, pages 627–636 (2023) https://www.nature.com/articles/s41586-023-06621-4

---

+++

Investigating mechanisms of bacterial cancer therapy

Supervisors: Kendle Maslowski and Ross McInnes

Project summary: The immune system protects us from infectious agents such as bacteria, viruses and fungi, as well as from malignant growth of our own tissues. Our lab is interested in the intersection between anti-bacterial and anti-tumour responses. The concept of bacterial cancer therapy dates to William Coley, who developed ‘Coley’s toxins’, a preparation of heat killed bacteria injected into tumours. Our work largely focuses on the use of live-attenuated Salmonella as a cancer therapy for colorectal cancer. We are dissecting the mechanisms by which attenuated Salmonella treatment leads to tumour regression, looking at the adaptation of the bacteria to the tumour environment, the effects on cancer cells and on immune responses. With a detailed mechanistic understanding of bacterial therapy, we aim to achieve optimal engineering of Salmonella to advance towards clinical application. The student will receive training in tumour organoid culture, bacterial growth and infection and analysis of cell phenotypes. More broadly the student will learn about host-microbe interactions in the gut.

References:

1. Copland A, Mackie GM, Scarfe L, Lecky DAJ, Gudgeon N, McQuade R, Ono M, Barthel M, Hardt W-D, Ohno H, Dimeloe S, Bending D, Maslowski KM. Salmonella cancer therapy metabolically disrupts tumours at the collateral cost of T cell immunity. bioRxiv. 2023;10.1101/2023.01.12.523780:2023.2001.2012.523780.

---

+++

Investigating Metabolic changes in PPARG Driven Prostate Cancer

Supervisors: Imran Ahmad and Tom MacVicar

Project summary: There exists a huge degree of prostate cancer cell metabolic remodelling to enable tumours to grow and combat androgen deprivation therapy. The mitochondria are essential organelles that support tumour adaptation, by dynamically reprogramming during tumorigenesis. Previous work in our group has identified the key role of the metabolic regulator PPARG in driving metastatic prostate cancer.

In this project, the candidate will use tumour models including genetically engineered mice to investigate how mitochondria contribute to tumorigenesis and treatment resistance. The candidate will study mitochondrial dynamics in these models with metabolomic and proteomic techniques. These studies will improve our basic understanding of metabolic changes in tumours and may identify novel therapeutic targets for prostate cancer.

References

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

---

+++

Live imaging cell death and its clearance during tissue remodelling and cancer.

Supervisors: Andrew J. Davidson and Stephen Tait

Project summary: Multi-cellular organisms are not created through cell proliferation alone. During development and tissue remodelling, healthy cells are deliberately removed through cell death in order to sculpt the tissue into its final form. However, if dead cells are not removed quickly through engulfment by other cells (such as macrophages), chronic inflammation is triggered. Therefore, the efficient clearance of cellular debris is vital for our health and wellbeing. Furthermore, in pathologies where cell death is elevated, overwhelmed clearance may exacerbate diseases such as cancer. In this project, we will use live-microscopy and the fruit fly, Drosophila melanogaster, to visualise the clearance of dead cells inside a living organism. Furthermore, we will combine advanced biosensors of cell death, the microinjection of dyes and Drosophila’s unrivalled genetics to investigate the importance of this clearance to development, tissue remodelling and tumourigenesis.

As part of this project, the student will gain extensive experience in live-imaging, including training on a variety of different confocal microscopes. Furthermore, the student will learn genetics, Drosophila husbandry and cell culture, as well as specialist techniques such as microinjection. The student will also receive mentoring on scientific critical thinking and writing. By the end of the project, the student will be well placed for a future career in biomedical sciences.

References

1. Heron, R., Amato, C., Wood, W. & Davidson, A. J. Understanding the diversity and dynamics of in vivo efferocytosis: Insights from the fly embryo. Immunol Rev, doi:10.1111/imr.13266 (2023).
2. Botto, M. et al. Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat Genet 19, 56-59, doi:10.1038/ng0598-56 (1998).
3. Raymond, M. H. et al. Live cell tracking of macrophage efferocytosis during Drosophila embryo development in vivo. Science 375, 1182-1187, doi:10.1126/science.abl4430 (2022).
4. Kurant, E., Axelrod, S., Leaman, D. & Gaul, U. Six-microns-under acts upstream of Draper in the glial phagocytosis of apoptotic neurons. Cell 133, 498-509, doi:10.1016/j.cell.2008.02.052 (2008).

---

+++

Metabolic adaptations of intestinal stem cells in health and disease.

Supervisors: Julia Cordero and Vignir Helgason

Project summary: Metabolism is a key determinant of cellular phenotype, amenable to nutritional and/or pharmacological therapeutic interventions. Although the impact of diet and metabolism in homeostatic intestinal stem cell (ISC) renewal and differentiation is well documented, the metabolic adaptations of ISCs to tissue injury and their influence on regeneration and cancer are largely unknown. While recent studies on mammalian systems have provided significant insight into ISC metabolism, these rely largely on in vitro cultures. The use of in vivo models is important to account for the influence of the natural microenvironment on ISC metabolism. Research on the adult Drosophila midgut — an organ with remarkable homology to the mammalian small intestine—has provided invaluable knowledge on ISC biology in health and disease. We use the adult Drosophila midgut as a high throughput in vivo paradigm for characterization of metabolic changes in ISCs following tissue damage and their functional role in intestinal regeneration and tumourigenesis. During this project, the student will receive theoretical and practical training in genetics, imaging, metabolism, intestinal biology, tissue regeneration and cancer.

References

1. Nászai M., Bellec K., Yu Y, Román-Fernández A., Sandilands E., Johansson J., Campbell A.D., Norman J.C., Sansom O.J., Bryant D.M., Cordero J.B1. RAL GTPases mediate EGFR-driven intestinal stem cell proliferation and tumourigenesis. Elife. 2021 Jun 7;10:e63807.
2. Perochon, J., Aughey, G.N., Southall, T.D., and Cordero, J.B1. Dynamic adult tracheal plasticity drives stem cell adaptation to changes in intestinal homeostasis. Nature Cell Biology, 23(5), pp. 485-496. (doi: 10.1038/s41556-021-00676-z). News and Views. Nature Cell Biology, 23, 580–582 (2021). doi.org/10.1038/s41556-021-00695-w
3. Parvy JP1, Yu Y, Dostalova A, Kondo S, Kurjan A, Bulet P, Lemaitre B, Vidal M, Cordero JB1. The antimicrobial peptide Defensin cooperates with Tumour Necrosis Factor to drive tumour cell death in Drosophila. Elife. 2019 Jul 30;8. pii: e45061. doi: 10.7554/eLife.45061. Recommended by the Faculty of 1000.
4. Scopelliti A1*, Bauer C*, Yu Y, Zhang T, Krüspig B, Murphy DJ, Vidal M, Maddocks OK, Cordero JB1. A neuronal relay mediates a nutrient responsive gut/fat body axis regulating energy homeostasis in adult Drosophila. Cell Metab. Oct 15. pii: S1550-4131(18)30629-6. doi: 10.1016/j.cmet.2018.09.021. Recommended by the Faculty of 1000.

---

+++

Role of INPP4b in PTEN-driven Prostate Cancer

Supervisors: Imran Ahmad and David Bryant

Project summary: The tumour suppressor gene PTEN is one of the most often deleted genes in human prostate cancer. Previous work from our groups have elucidated how PTEN loss, often with co-operating mutations, can drive metastatic prostate cancer. Our recent work, using a forward transposon-based screen, has identified loss of INPP4b co-operating with PTEN loss to drive treatment resistant prostate cancer. In this innovative project, the candidate will use 3D tumour models combined with orthotopic mouse models to investigate how INPP4B loss contributes to prostate tumourigenesis in a PTEN loss background. The candidate will study enzymes involved in phosphatidylinositol signaling pathways, to improve our basic understanding of this pathway in tumours and may identify novel therapeutic targets for prostate cancer.

References

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
2. Roman-Fernandez A, Roignot J, Sandilands E, Nacke M, Mansour MA, McGarry L, Shanks E, Mostov KE, Bryant DM. The phospholipid PI(3,4)P2 is an apical identity determinant. Nat Commun. 2018; 9: 5041.
3. Ahmad I, Mui E, Galbraith L, Patel R, Tan EH, Salji M, Rust AG, Repiscak P, Hedley A, Markert E, Loveridge C, van der Weyden L, Edwards J, Sansom OJ, Adams DJ, Leung HY. Sleeping Beauty screen reveals Pparg activation in metastatic prostate cancer. Proc Natl Acad Sci USA. 2016; 113: 8290-5. 

---

Overview

Programme description

Students will undergo 1-year of full-time research in a laboratory chosen from our supervisory pool of world-renowned principal investigators. A further year is allowed for thesis writing.

In addition to their research time, students will have the opportunity to participate in research seminars [Glasgow Cancer Seminar Series], tutorials, science retreats and interactive discussion groups. Bioinformatic, research integrity and data management training courses are also offered to PGR students. Our skills pathway sets out recommended courses at different stages of PGR research study.

Students will have a primary and secondary research supervisor and 2 reviewers, who will oversee annual research progress. Students will give an introductory talk after the initial review panel meeting and within 4 months of starting their research year. At the end of their research year, students will write a MSc by Research thesis report (max 50,000 words) to be assessed by an internal and external examiner. The examiner may require a viva voce. Students will have up to 12 months after their year of laboratory research to fulfil these requirements for degree award.

Application deadline

Applications will be open from 1 October 2024 - 30 April 2025

School of Cancer Science

You will study in state-of-the-art laboratory space at our School of Cancer Sciences. The school provides multiple centralised facilities operated by expert managers.  These include tissue culture, flow cytometry, imaging, metabolomic, proteomics, genomics, high content screening, histology facilities and biological service unit.

We bring together world-leading fundamental stem cell, inflammation, cancer and tissue regeneration research with established clinical and discovery research excellence.

The School of Cancer Sciences includes:

• Beatson CRUK Scotland Institute,
• Wolfson Wohl Cancer Research Centre
• Paul O’Gorman Leukaemia Research Centre. 

Learning outcomes

Towards the end of the programme, students will have been exposed to and acquire a wealth of laboratory research techniques and conceptual learning knowledge.  These will include but not be limited to the following:

Technique learning

• 3D organoid technology
• Advanced imaging
• Biochemistry
• Bioinformatics
• Cell and primary tissue culture
• Cell biology
• Cell Sorting
• Genomic engineering (CRISPR, RNA interference)
• Mass spectrometry
• Molecular biology
• Molecular genetics
• Statistics
• Tissue culture
• Use of genetically engineered mouse models for research
• Use of non-mammalian model organisms for research, such as the fruit fly Drosophila melanogaster.
• Various Omics (proteomics, metabolomics, transcriptomics)

Conceptual learning

• Cancer biology
• Cell death and mitochondrial biology
• Cell metabolism
• Drug screening and development
• Immunology
• Regenerative biology
• Stem cell biology
• Whole body physiology

Programme management team

Programme Director: Prof. Julia Cordero, Professor of Systemic Signalling Biology.

The programme is supported by:

• Professor Joanne Edwards, Professor of Translational Cancer Pathology and Director of Education
• Professor Helen Wheadon, Professor of Stem Cell Regulation and Deputy Director of Education
• Dr Heather Jorgensen, Senior Research Scientist and Post-Graduate Research Convenor
• Mrs Anne Best, Senior Administrator

Study options

MSc (Research)

• Duration: 1 year full-time; 2 years part-time