Acknowledgements: This study was supported by Prostate Cancer UK (PCUK; Grant PA14-012), Cancer Research UK (CRUK; Grant C19212/A27150), AstraZeneca, and the National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Centre (BRC; Grant NIHR203312). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. N.S. was supported by the Gates Cambridge Trust and is now a Research Fellow of Emmanuel College, Cambridge. A.Y.W. is supported by the Urological Malignancies Programme of the Cancer Research UK Cambridge Centre (C9685/A25177) and NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). V.J.G. acknowledges infrastructure support from the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). Additional support provided from the Cancer Research UK Cambridge Centre, the Cambridge Experimental Cancer Medicine Centre, a Wellcome Trust Strategic Award, Addenbrooke’s Charitable Trust, the Canadian Institute For Advanced Research, and Cambridge University Hospitals National Health Service Foundation Trust. The authors thank Dr Julia Jones of the Cancer Research UK Cambridge Institute for her help with the RNAscope component of the study.AbstractHyperpolarised magnetic resonance imaging (HP-13C-MRI) has shown promise as a clinical tool for detecting and characterising prostate cancer. Here we use a range of spatially resolved histological techniques to identify the biological mechanisms underpinning differential [1-13C]lactate labelling between benign and malignant prostate, as well as in tumours containing cribriform and non-cribriform Gleason pattern 4 disease. Here we show that elevated hyperpolarised [1-13C]lactate signal in prostate cancer compared to the benign prostate is primarily driven by increased tumour epithelial cell density and vascularity, rather than differences in epithelial lactate concentration between tumour and normal. We also demonstrate that some tumours of the cribriform subtype may lack [1-13C]lactate labelling, which is explained by lower epithelial lactate dehydrogenase expression, higher mitochondrial pyruvate carrier density, and increased lipid abundance compared to lactate-rich non-cribriform lesions. These findings highlight the potential of combining spatial metabolic imaging tools across scales to identify clinically significant metabolic phenotypes in prostate cancer.</jats:p
