Edinburgh Cancer Research

The role of dynamic changes in proteome in pancreatic cancer initiation

Dr S Wilkinson, Prof Jennifer Morton, Prof Zara Zanivan

Simon Wilkinson Research image

About the Project


Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate under 7%. Better understanding of PDAC formation will help improve this.

PDAC can begin upon Kras oncogene mutation in pancreatic acinar cells. However, initial changes in mutant cells appear quite limited. Only after unidentified molecular events, either occurring stochastically or consequent from injury, do cells eventually undergo large scale morphological change in a process called acinar-ductal metaplasia (ADM). This precedes PDAC formation

These molecular events enabling ADM have been inferred from transcriptomic data obtained from genetically-engineered mouse (GEM) models of PDAC. However, it is difficult to differentiate initial driving events from the large scale changes consequent from ADM. Additionally, our data identify that some important molecular changes predisposing to ADM occur at the protein, rather than transcript, level. Furthermore, some such protein changes are only detectable transiently in rare cell subpopulations.


The student will perform proteomic characterisation of novel mouse models of PDAC initiation that are synchronised in the pre-ADM state. Thus, they will uncover the proteome changes that trigger initiation of pancreatic cancer.


The lab has previously used a well-studied GEM model of PDAC wherein we could accelerate and synchronise pre-ADM cell states by deleting Atg5 or Ccpg1 (genes involved in proteostasis). This has enabled the lab to use mass spectrometry on whole pancreata to identify proteome changes linked to cancer formation. However, this model is limited as it relies on mutation of an oncogene across most of the pancreas. This leads to confounding, wide-ranging changes in proteome consequent from “runaway” inflammation and tissue degeneration. This obscures much of the important data. Therefore, the student will employ state-of-the-art, unpublished models that circumvent this difficulty by only mutating an oncogene and/or proteostasis genes in a rarer population of cells. They will then be able to identify key protein changes in just this subpopulation of cells within the pancreas.

In detail, the student will use virus bearing an acinar cell-specific promoter to initiate tumourigenesis in a carefully titered proportion of cells. In the first approach, this virus will also result in marking of targeted cells with GFP (green fluorescent protein). We will then use fluorescence-based sorting of these cells to isolate this rare population for mass spectrometry (pooled and single-cell). The student will also evaluate a parallel approach using a new MetRS* transgene. This allows expression of artificial tRNA incorporating non-canonical amino acids into target cell proteins, facilitating identification of the proteome of only the cells transduced with virus. Finally, a third model will be employed, wherein a biotinylating enzyme (ss-TurboID-KDEL) will be expressed within acinar cells. Blood plasma proteomics will be performed to detect biotinylated proteins and thus infer the altered secretory proteome of pre-ADM cells.

The functional role of selected proteins in driving ADM will be tested by using virus-mediated shRNA delivery in loss-of-function experiments. Key protein changes will be assessed in pancreatic samples from surgical patients, many of which bear precancerous changes, thus translating the findings to human tissue.

Application procedure

Up to 4 studentships are available to start in September 2023 for outstanding applicants with a stipend of £21,000 p/a. These 4 STUDENTSHIPS are funded by the CRUK Scotland Centre, a joint initiative between Edinburgh and Glasgow. Successful students for Edinburgh lead projects will be registered for their degree in Edinburgh and will undertake their project in Edinburgh. 

Candidates should hold at least an upper second-class degree in a relevant subject and comply with University of Edinburgh English language requirements.

For further information on how to apply, please visit: https://www.ed.ac.uk/cancer-centre/graduate-research-and-training/cancer-research-uk-phd-programme

Simon Wilkinson Research Group