- The impact of cellular metabolic pathway manipulation on inflammatory-driven Barrett’s Oesophagus (BO)-to-Oesophageal cancer (OAC) transitioning, and the potential role for the HDL proteome as a non-invasive immune-metabolic biomarker of disease progression.
Dr Fiona McGillicuddy
AllCaN Oesophageal Principal Investigator
Prof. Helen Roche
AllCaN Oesophageal Principal Investigator
Ms. Pousali Chatterjee
AllCaN Oesophageal PhD Candidate
- January 2024 (4 years)
Research question
Can we improve the identification of survivors who most need dietary support using personalised biomarkers, and is it visceral adiposity or dietary saturated fatty acids that augment the risk of transition from BO to OAC?
Overview – Part 1
Diet-induced versus obesity-induced metabolic/inflammatory triggers promoting the transition from BO to OAC
Diet will not cure established OAC, but dietary insults may trigger early carcinogenic changes in BO, potentiating conversion to OAC. While obesity is a well-known risk factor, the contributory role of dietary fats is largely unknown. Saturated fatty acids (SFA) and cholesterol crystals are well-characterised inducers of IL-1β-driven inflammation, a key component of carcinogenic inflammation. Alternatively, an increase in visceral adipose tissue (VAT), which develops due to an excess of certain dietary elements, particularly SFA may be key. It is not currently known whether it is a specific effect of SFA per se or an indirect effect of increasing VAT. This is important information to define future preventative dietary interventions.
To address this hypothesis we will conduct a study to understand how the metabolic microenvironment impacts the proliferation rates and inflammatory state in early-stage BO and later-stage OAC cell models. We aim to determine how changes in cellular glycolysis and/or fatty acid
oxidation and/or cholesterol metabolism influence cellular proliferation rates and inflammatory status. We will examine the impact of exposure to different nutritional stimuli, such as a) pro-inflammatory SFA versus monounsaturated (MUFA) and polyunsaturated (PUFA) fatty acids, or VAT-derived metabolic milieu; b) acetylated LDL-cholesterol or HDL-cholesterol, and c) low- and high glucose/insulin on cellular proliferation rate and inflammation (IL-8/IL-1β read-outs) as well as cellular proteomic pathway signatures. We will establish whether manipulation of metabolic pathways can influence IL-1β/IL-18 priming within BO/OAC cell-lines as well as modulate response to these inflammatory triggers.
Our goal is to use this information to develop early nutritional interventions in high-risk patients to prevent the transition from health to disease in obesity-related oesophageal cancer.
Overview – Part 2
HDL proteomic biomarker profiling to better define response to lifestyle interventions
The McGillicuddy group, in collaboration with Prof. Stephen Pennington, has recently built a novel risk stratification platform for people living with obesity (PwO) that can sensitively detect metabolic inflammation in obesity by directly measuring the proteins (n=82) attached to circulating high-density lipoprotein (HDL) particles (patent granted, manuscript in preparation). Importantly, ~30% of HDL particles are derived from the intestine. In this project, HDL proteomics will be completed on the ReStOre intervention cohort (in collaboration with Prof Juliette Hussey). ReStOre is a multi-modal intervention integrating both exercise and nutritional support – therefore it is an ideal study to complete more intensive biomarker profiling to optimise the assessment of response to lifestyle interventions. This is a large intervention trial supported by HRB and in which a survivorship biobank has been created. HDL proteomics is a sensitive tool capable of characterising metabolic-inflammatory signatures – this will be extended to discern its utility to track synergistic nutritional-physical activity interventions in n=120 patients recovering from upper GI cancers, including oesophageal. Outcomes collected pre- and post-intervention including physical strength, fitness, nutritional status, dietary intake, and quality of life indices. HDL proteomics will be completed at the UCD Conway proteomics core using pre-established study protocols by the McGillicuddy group. Novel proteomic signatures will be integrated with the basic clinical data already available – bioinformatics will be focused on better-identifying risk and response to the physical and dietary interventions.
Anticipated impact of this AllCaN Oesophageal research project
This ReStOre programme will allow us to determine if / how this precision nutrition / biomarker approach might also reflect combined diet-physical activity interventions. HDL proteomics will track synergistic nutritional and physical activity interventions in survivors. A better understanding of the dietary effects and adipose tissue biology will help better understand if obesity in BO increases risk.