Developing endothelial AMBRA1 as a biomarker for early-stage melanoma with metastatic potential and understanding the molecular mechanisms potentiating endothelial loss of AMBRA1

Up to 15% of patients with stage I/II melanoma will develop metastatic disease, for which there are no credible biomarkers. The combined epidermal expression of AMBRA1 and Loricrin (AMBLor) has been validated as a prognostic biomarker able to identify low risk subsets of patients with non-ulcerated stage I/II melanomas but is unable to identify those at high risk of metastatic progression. With this award I evaluated the potential of peri-tumoural endothelial AMBRA1 expression as a prognostic biomarker of melanoma metastasis, using semi-quantitative immunohistochemistry methodology on a retrospective cohort of formalin-fixed paraffin-embedded melanomas.

Additionally, transforming growth factor (TGF)-β2 has been shown to mediate the loss of epidermal AMBRA1. To test the hypothesis melanoma secreted TGF-β superfamily ligands cause downregulation of endothelial AMBRA1, I screened two metastatic melanoma cell lines for TGF-β associated genes. Preliminary qPCR array data identified bone morphogenic proteins (BMP) 2, 6 and 7 as potential mediators for the loss of AMBRA1 in the tumour microenvironment, warranting further investigation.

This award enabled me to derive pump-priming data that led to my successful award of the 2023 CRUK Pre-doctoral Research Bursary and 2024 Newcastle University-CRUK Clinical Academic Training (NU-CAT) PhD fellowship, allowing me to continue my research in this field.