Exploiting pyrimidine metabolism as a cancer prevention and intervention strategy

Background: In the earliest stages of premalignant progression, changes in the microenvironment play a key role in supporting tumour initiation. These favourable environments prime niches to facilitate carcinogenesis.

Understanding the physiology of cells that contribute to these altered environments provides opportunities to discover biomarkers that identify patients at high-risk of cancer emergence, in addition to highlighting prevention intervention opportunities.

Neutrophils are a key microenvironmental component, and elevated neutrophil:lymphocyte ratios have been identified as a poor prognostic factor in cancer.

We have data to suggest that alterations in neutrophil metabolism occur early in disease development, and these metabolic alterations are key to creating environments that facilitate carcinogenesis.

Specifically, we find that catabolism of pyrimidines is increased in activated neutrophils, with elevated expression of uridine phosphorylase 1 (UPP1), an enzyme which cleaves uridine into uracil and ribose-1-phosphate, detected in neutrophils from tumour-bearing mice compared to wild-type controls.

Importantly, we find that UPP1 high neutrophils demonstrate altered behaviours which generate microenvironments that enable cancer cells to colonise tissues. Aims: Increased neutrophil numbers are measurable before detection of tumours in mouse models of mammary cancer.

This project therefore aims to assess the ability of UPP1 to shape the pre-cancerous landscape and understand whether inhibition of UPP1 can prevent tumourigenesis.

We will then translate these findings into human patients, to understand whether circulating uracil levels (a measure of UPP1 activity) are characteristic of early cancer, to inform the utility of uracil to identify high-risk patient populations.

Methods: Utilising our expertise in mouse models of cancer, and access to human patient samples, we will characterise immune and metabolic changes in the pre-cancerous landscape, their dependence on UPP1 expression, and understand whether UPP1 inhibition is an efficacious method of cancer prevention.

How the results will be used: Using breast cancer as a case example, this project will provide proof-of-principle data for UPP1 inhibition as a preventative intervention, and UPP1 activity as an identifying feature of high-risk patients. This study requires the use of cancer models and patients for proof-of-principle.

However, given that neutrophilia is a feature of many pathologies including infection, inflammation, obesity and smoking-related diseases, delivery of this project will support a larger programme of work to understand which neutrophilic populations also have high UPP1 activity and would consequently benefit from UPP1 inhibition as a prevention approach to decrease risk of cancer development as part of their standard of care.