Prof Jim Norman & Dr Cassie Clarke
Labs: Integrin Cell Biology
Duration: 4 years, starting Oct 2023
Closing Date: 6th January 2023
Metastatic spread to the lung remains a major contributor to breast cancer morbidity and mortality. Prior to development of clinically-evident metastases, occult disseminated tumour cells must first colonise the lung, survive and proliferate and this is enabled through a complex interplay between the primary tumour, stroma and myeloid cells, particularly neutrophils, creating a favourable microenvironment for metastasis – called the pre-metastatic niche.
Results leading up to project
We screened for circulating metabolites that were associated with pre-metastatic niche priming in mouse models of mammary cancer. This indicated that increased circulating levels of the pyrimidine, uracil are linked to lung metastasis. Further studies revealed that increased circulating uracil in metastasising mice is generated by mobilisation of neutrophils expressing uridine phosphorylase-1 (UPP1) - an enzyme which cleaves uridine into uracil and ribose-1-phosphate. Moreover, we have found that UPP1 alters neutrophil recruitment to the lung – and their accumulation within the lung vasculature - in mice bearing mammary carcinoma, and that neutrophil accumulation precedes metastasis.
The student will investigate the adhesive/migratory behaviour of neutrophils in the lung vasculature of mice with mammary carcinoma and determine how this is controlled by UPP1. The student will use ex vivo live cell imaging of precision-cut lung slices to image neutrophil movement in the lung vasculature of wild-type and UPP1 knockout mice bearing mammary tumours. Further mechanistic studies will be conducted by using microfluidic approaches to measure neutrophil interaction with lung endothelial cells to determine how the UPP1 product, uracil, influences the adhesive and migratory machinery of neutrophils and endothelial cells. Finally, the student will work in collaboration with the CRUK Beatson Institute's proteomics facility to develop analytical approaches to identify potential uracil-binding proteins/receptors which may be responsible for influencing the adhesive and/or migratory machinery of neutrophils or lung endothelial cells.
Opportunities for patient benefit
We believe that the biological insight gained through these studies will enable us to determine the potential for using UPP1 inhibitors to oppose or reverse metastatic niche priming in breast cancer, thus decreasing the chance of metastatic recurrence following primary tumour resection.