Seeking improved outcomes in pancreatic cancer: Applying multi-omic data analysis approaches to explore the biology underpinning pancreatic cancer-related diabetes

Description

Pancreatic cancer is the deadliest of the common cancers. Sadly for 80% of patients, by the time their cancer is diagnosed it has spread to distant organs making them ineligible for potentially curative surgery. Methods to detect pancreatic cancer earlier are badly needed ¹.

With no population-wide screening or effective treatment, an enhanced understanding of the biology of this cancer is required.

An unexplained feature of pancreatic cancer is its ability to cause hyperglycaemia (raised blood glucose). At the time of cancer diagnosis, over 45% of patients have diabetes. Typically, diabetes is of new-onset, and is considered to be a ‘symptom’ of pancreatic cancer, known as type 3c diabetes.

We hypothesise that pancreatic cancers that do not raise blood glucose (non-diabetogenic tumours) have different molecular programs compared to their diabetogenic (diabetes-causing) counterparts.

The Costello Laboratory, focussed on early detection of pancreatic cancer, leads a Cancer Research UK-funded programme (United Kingdom Initiative for Early Detection of Pancreatic Cancer, UK-EDI ²) aimed at building resources for earlier detection of pancreatic cancer in individuals with new-onset diabetes. Single-cell gene expression analysis from pancreatic tumours, stratified by diabetes (Pancreatic Cancer UK-funded),³ and parallel analysis of blood protein profiles to identify genes and pathways dysregulated in pancreatic cancer-related diabetes is ongoing.⁴

Objectives

1. Perform state-of-the-art bioinformatic analysis of single cell gene expression and blood-based proteomic data, selecting candidate markers that exemplify differences between diabetogenic versus non-diabetogenic pancreatic cancer
2. Undertake pathway analysis to investigate novel mechanisms involved in pancreatic cancer-related diabetes
3. Undertake laboratory validation of molecular findings

Novelty

The interrogation of the molecular pathways associated with pancreatic cancer-related diabetes is novel. Understanding how pancreatic cancer causes diabetes and its associated molecular consequences will significantly advance the field. Comparing newly obtained tissue and blood data will allow identification/explanation of potential biomarkers for early detection. The application of extensive bioinformatic analysis followed by spatial transcriptomic to this research question is entirely novel.

Timeliness

The DiMeN studentship will synergise with other research, including a Cancer Research UK programme, which has built resources and generated data addressing pancreatic cancer-related diabetes (led by the primary supervisor). Despite individuals with new-onset diabetes being the largest high-risk group for pancreatic cancer, major gaps in knowledge prevent screening of this group. Progress in understanding the biology underpinning diabetes secondary to pancreatic cancer could facilitate future interventions in early pancreatic cancer detection and treatment.

Experimental Approach

The student will undertake established training courses run by Computational Biology Facility ⁵. and be trained in the analysis of large transcriptomic and proteomic datasets (by the secondary supervisor). The integration of single cell data (n=8 cases) and blood protein data (n=210 subjects, >7500 proteins/subject) will provide a unique and comprehensive view of molecular pathways underpinning pancreatic cancer-related diabetes. Differences in gene expression and protein levels between diabetogenic and non-diabetogenic tumours will be validated by targeted analysis in independent cancers. This will include use of standard methodologies (Western blotting, ELISA) as well as a novel 10x visium spatial transcriptomics (>200 samples stratified for diabetes).

Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: https://www.dimen.org.uk/blog

Further information on the programme and how to apply can be found on our website: https://www.dimen.org.uk/how-to-apply