Cancer Research UK Edinburgh Centre

CRUK 4 year PhD opportunities - apply now

Applications now welcome for 2017 CRUK studentship programme - closed now: January 2017

IGMM PhD studentships

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Closing date: 13 February 2017

Five projects (descriptions below) are being offered for 2 or 3 studentships at the Cancer Research UK Edinburgh Centre at the University of Edinburgh starting in September 2017. The studentships will cover tuition fees for UK/EU residents, research expenses and travel, plus a generous £19,000 per annum stipend.

Potential projects and supervisors are as follows:

Adhesion protein biology in human pancreatic cancer – Professor Margaret Frame, Dr Bryan Serrels and Dr Adam Byron

Pancreatic cancer remains poorly responsive to current therapies, and there is an urgent need to understand the biology of this dismal disease. We will therefore examine adhesion networks in genetically defined human pancreatic cancer cells (provided by Prof Andrew Biankin, University of Glasgow; see Bailey et al., Nature, 2016 Mar 3;531(7592):47-52). By using mass spectrometry and iterative network analyses, we will link genotypes to adhesion protein networks, asking, for example, whether specific driver mutations are associated with predominance of particular adhesion protein complexes and/or complexes between adhesion proteins and nuclear transcription factors (as we have found in Squamous Carcinoma Cells (SCCs); Cell, 2015 Sep 24;163(1):160-73).

We will define the status of the four pillars of the recently defined consensus adhesome (Nat Cell Biol, 2015 Dec;17(12):1577-87) in pancreatic cancer cells of different pathological grades. To characterise pancreatic cancer adhesion networks, we will isolate protein complexes associated with the adhesion receptor beta-1 integrin (engaged with its ligand fibronectin and stabilised using crosslinker) and immunoprecipitate key components of the four axes of the consensus adhesome, namely FAK, Kindlin, -actinin, and Talin. We will use mass spectrometry to identify their common and distinct binding partners, assessing how these differ between disease sub-types and across the mutational spectrum. To identify ‘close’ or direct interactors, we will make use of proximity-dependent biotinylation, biotin capture and mass spectrometry (BioID). BioID will also ensure we capture weak or transient interactions, and will offer the opportunity to perform temporal studies, such as assessing the changing landscape of the interactome upon treatment with clinically relevant compounds. Furthermore, we will establish “adhesion” protein complexes associated with nuclear scaffolding functions and transcriptional regulation, such as those recently shown for FAK (and others found recently in SCCs (our unpublished data)). This project will dovetail with others examining adhesion protein complexes found both at the cell periphery to regulate cell migration and invasion and in the nucleus to regulate transcription.

Once we identify direct binding partners of consensus adhesome nodes that are linked to genotypically-defined pancreatic cancer, we will use CRISPR-mediated gene deletion to intervene, deleting the nodes and/or their key interacting partners. We will determine the transcriptional and biological effects of interventions that, in combination, are predicted to collapse the robustness of ‘the adhesome’ in pancreatic cancer cells.

The overall aims of this project are to understand: i) consensus adhesion networks in genetically-defined pancreatic cancer cells, ii) whether they control transcription, and iii) their role in influencing tumour cell behaviour in vitro and in vivo, including growth, invasion and metastasis. The training wll encompass wet lab state-of-the-art cancer biology, proteomics and computational bioinflrmatics/protein network analyses. Where there are suitable drug targets amongst the adhesion nodes or their key interacting partners in pancreatic cancer cells, we will link to CRUK-funded drug discovery programmes.

Understanding the function of new autophagy players and their relevance in brain tumours – Dr Noor Gammoh

Glioblastoma multiforme (GBM) is the most common and aggressive brain tumour with a median survival of approximately one year. Mutations in multiple signalling pathways have been identified in GBM that fuel cell proliferation and enhance survival. Understanding downstream survival response processes in GBM that contribute to its resistance would be crucial for therapy. One such process is autophagy, literally meaning “self-eating”, which acts as a cellular disposal mechanism of various components including damaged organelles, unfolded proteins and pathogens. During autophagy, vesicles known as autophagosomes form and engulf cytoplasmic material leading to their lysosomal degradation. The degradation products are recycled back in the cell providing energy and nutrients supply which is of particular importance to cells undergoing stress. Because of these properties, autophagy has been implicated in various pathological conditions including auto-immune response, neurodegeneration and cancer.

The lab is particularly interested in understanding how autophagy can implicate GBM growth and survival and its possible targeting during anti-cancer treatment. The lab utilises a number of key systems including animal modelling, patient-derived cells and CRISPR/Cas9-mediated gene editing. Using gRNA screens and proximity labelling assays, the lab aims to understand factors that regulate autophagy induction and can be potentially used as therapeutic targets. A PhD project is available to investigate novel players that have been identified in the lab by understanding how they function in regulating autophagosome formation. The project will involve various cell and molecular biology techniques including tissue culture, protein and DNA techniques (including western blotting and cloning), oncogenic growth assays, cell death/survival, confocal microscopy (live and fixed fluorescent imaging) and CRISPR/Cas-mediated gene editing.

Identification of the cell of origin in MLL-AF9-associated infant leukaemia – Dr Katrin Ottersbach

Although blood cancer in infants is rare, it poses a challenging clinical problem. Compared with older children, infants with leukaemia usually present with a more aggressive disease that frequently relapses following treatment. It is known that the disease in infants initiates before birth in a foetal blood cell that has unique properties that contribute to the aggressiveness of the cancer. To be able to develop new treatments that specifically benefit infant patients, it is therefore essential to identify the cell of origin for infant leukaemia, to define its unique properties and to understand how the development of the blood system is affected in infant patients. The aim of this project is to investigate the effect that a mutation commonly found in infant leukaemia, the MLL-AF9 fusion oncogene, has on foetal blood development in a mouse model. Our preliminary data suggest that MLL-AF9 increases blood progenitor output, that it can change the differentiation path of blood progenitors and that it can even cause a block in differentiation, a phenomenon found in many cancers.  Furthermore, these effects are very much dependent on the cell type in which MLL-AF9 is expressed. In this project, the student will investigate the effect MLL-AF9 has on foetal blood development in more detail. Importantly, s/he will test if different foetal blood cells that carry the mutation can cause the cancer in a similar manner. Finally, s/he will explore the molecular factors within the cell of origin that assist the mutation in turning it into a cancer cell and interrogate these as potential new drug targets.

Determining the effects of mutations on the epigenome in cancer – Dr Duncan Sproul

Epigenetic dysfunction is a fundamental hallmark of cancer that is associated with the repression of tumour suppressor genes. For example, DNA methylation alterations are intrinsic to breast carcinogenesis and are associated with silencing of the tumour suppressor gene BRCA1. However, we do not understand how these potential epimutations occur. We have shown that epigenetic marks are strongly programmed by the genome, most likely through the action of transcription factors (Benveniste et al 2014 PNAS PMID: 25187560). A consequence of this finding is that mutations can cause local alterations in DNA methylation levels. This project seeks to use such mutations as tools to understand the interaction between DNA methylation and transcription factors. We will combine computational analyses of germ-line and somatic sequence variants with genome-editing technologies to determine which mutations affect DNA methylation, identify the proteins responsible and how these interactions affect transcription and cancer phenotypes. The project provides the opportunity for the student to acquire expertise in a range of cutting edge techniques including CRISPR genome and epigenome editing, high throughput sequence analysis and machine learning.

Modelling systemic molecular changes underlying prognosis in lung cancer

Lung tumours secrete as-yet-unknown factors into the blood to promote wasting of distant tissues and systemic weakening (“cachexia”), rendering treatments ineffective. Disease prognosis could be considerably improved by identifying and targeting these factors (1,2). Candidates for these secreted factors include proteins and metabolites.

You will use a genetically-engineered mouse model of lung adenocarcinoma that exhibits gradual deterioration in condition due to cachexia (3). In the first year of the project you will screen plasma samples from tumor-bearing and control mice to identify factors over-represented within the circulation of the former group. You will use unbiased mass-spectrometry based proteomics and metabolomics, and sensitive targeted protein detection technology (reverse-phase protein arrays). In parallel, syngeneic cancer cell lines will be established from tumor-bearing mice displaying cachexia and tested for their ability to drive tissue wasting upon re-implantation in mice. RNA-seq will be performed to obtain differential gene expression profiles associated with the ability to drive cachexia.

In the second stage of the project, you will shortlist the most promising identified factors for direct testing of their involvement in cachexia, including confirmation of their provenance (i.e. directly from tumor cells or produced by the tumour stroma). Criteria for prioritisation will include deregulation of levels and correlation with objective measures of cachexia in human lung cancer patients (samples/data provided by collaborators in the Palliative Care Group). Production of factors produced directly by the tumor cells themselves will be manipulated by CRISPR/Cas9 in syngeneic cell lines, or by genetic or pharmacologic approaches in the mouse model. Thus we will gain valuable insights into potential approaches to improve prognosis via tackling the molecular aberrations of lung cancer at a whole system level.


  1. Petruzzelli & Wagner (2016). Genes Dev 30: 489
  2. Kir et al (2014). Nature. 513: 100
  3. Petruzzelli et al (2014). Cell Metabolism. 20: 433

How to Apply

Students should have, or expect to obtain a good Upper Second or First Class degree. Applicants should send a covering letter, stating why they are interested in the project, along with an up-to-date CV which includes contact details of two academic referees to by 13th February.  Interviews will be held on Friday 3rd March.

*Please note that applicants do not need to submit more than one application if they are interested in more than one project.

Applicants must also submit an online application to our PhD programme via EUCLID – instructions can be found here

We will not consider applications that have not been submitted to both and EUCLID by the closing date.

If you have not heard from us by 3 March please consider your application unsuccessful (we will not be able to provide feedback on unsuccessful applications).