Poster only 3rd Metabolic Diseases; Breakthrough Discoveries in Diabetes & Obesity 2022

Metabolic tracing of prostate cancer patient-derived xenografts identifies metabolic heterogeneity and highlights the therapeutic potential of targeting fatty acid metabolism (#118)

Gio Fidelito 1 , David P. De Souza 2 , Renea A. Taylor 3 4 , Matthew J. Watt 1
  1. Anatomy and Physiology, The University of Melbourne, Melbourne, Victoria, Australia
  2. Metabolomics Australia, Bio21 Institute, University of Melbourne, Melbourne, Victoria, Australia
  3. Physiology, Biomedicine Discovery Institute, Cancer Program, Monash University, Melbourne, Victoria, Australia
  4. Prostate Cancer Research Program, Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

Cancer cells undergo metabolic reprogramming, altering their flux through various metabolic pathways in order to meet the increased bioenergetic demands to support proliferation and survival. Studies in cell lines and mouse models have highlighted the importance of oxidative metabolism and lipogenesis in prostate cancer, however, the metabolic landscape of human prostate cancer remains unclear. To address this knowledge gap, we performed radiometric (14C) and stable (13C) isotope tracing assays in precision-cut slices of patient-derived xenografts (PDXs) representing different stages of disease (i.e., benign, localised, and metastatic).

Glucose, glutamine, and fatty acid oxidation was variably upregulated in malignant PDXs compared to benign PDXs, while lactate oxidation was unchanged. De novo lipogenesis (DNL) and storage of free fatty acids into complex lipids, most notably phospholipids and triacylglycerols, were increased in malignant PDXs compared to benign PDXs. There was no difference in substrate utilisation between localised and metastatic PDXs and hierarchical clustering revealed marked metabolic heterogeneity across all PDXs. In agreement with the 14C tracer data, malignant PDXs exhibited higher incorporation of 13C-labelled substrates into TCA cycle intermediates. Mechanistically, glucose utilisation was mediated by acetyl-CoA production rather than carboxylation of pyruvate, while glutamine entered the TCA cycle through transaminase reactions before being utilised bidirectionally (oxidative and reductive). Notably, transcriptomics was ineffective at predicting metabolic rates of PDXs. Using common metabolic inhibitors, we next showed that blocking fatty acid uptake or fatty acid oxidation was sufficient to reduce cell viability in all PDX-derived organoids (PDXOs) examined, whereas blockade of DNL, or glucose or glutamine oxidation induced variable and limited therapeutic efficacy in PDXOs.

These findings demonstrate that human prostate cancer, irrespective of disease stage, can effectively utilise all metabolic substrates, albeit with marked heterogeneity across tumours. We also confirmed fatty acid uptake and oxidation as targetable metabolic vulnerabilities in human prostate cancer.