Hyperpolarised 13C-MRI identifies the emergence of a glycolytic cell population within intermediate-risk human prostate cancer
Nikita Sushentsev, Mary A. McLean, Anne Y. Warren, Arnold Julian Vinoj Benjamin, Cara Brodie, Amy Frary, Andrew B. Gill, Julia Jones, Joshua Kaggie, Benjamin W. Lamb, M. Locke, Jodi L. Miller, Ian G. Mills, Andrew N. Priest, Fraser Robb, Nimish Shah, Rolf F. Schulte, Martin J. Graves, Vincent J. Gnanapragasam, Kevin M. Brindle, Tristan Barrett, Ferdia A. Gallagher
Abstract
Abstract Hyperpolarised magnetic resonance imaging (HP 13 C-MRI) is an emerging clinical technique to detect [1- 13 C]lactate production in prostate cancer (PCa) following intravenous injection of hyperpolarised [1- 13 C]pyruvate. Here we differentiate clinically significant PCa from indolent disease in a low/intermediate-risk population by correlating [1- 13 C]lactate labelling on MRI with the percentage of Gleason pattern 4 (%GP4) disease. Using immunohistochemistry and spatial transcriptomics, we show that HP 13 C-MRI predominantly measures metabolism in the epithelial compartment of the tumour, rather than the stroma. MRI-derived tumour [1- 13 C]lactate labelling correlated with epithelial mRNA expression of the enzyme lactate dehydrogenase (LDHA and LDHB combined), and the ratio of lactate transporter expression between the epithelial and stromal compartments (epithelium-to-stroma MCT4). We observe similar changes in MCT4, LDHA, and LDHB between tumours with primary Gleason patterns 3 and 4 in an independent TCGA cohort. Therefore, HP 13 C-MRI can metabolically phenotype clinically significant disease based on underlying metabolic differences in the epithelial and stromal tumour compartments.