In-person Flash Talk & E-Poster Presentation 34th Lorne Cancer Conference 2022

Hungry for more: Increased oxidative metabolism and TCA cycle activity in prostate cancer (#15)

Gio Fidelito 1 , David P. De Souza 2 , Malcolm J. McConville 2 3 , Renea A. Taylor 4 5 6 , 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. Biochemistry and Pharmacology, The University of Melbourne, Melbourne, Victoria, Australia
  4. Physiology, Biomedicine Discovery Institute, Cancer Program, Monash University, Melbourne, Victoria, Australia
  5. Prostate Cancer Research Program, Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  6. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia

Metabolic dysregulation as a hallmark of all cancers enables metabolic reprogramming to sustain proliferation and support progression. As previously observed in immortalised cell lines and mouse studies, prostate cancer exhibits unique metabolic adaptation from aerobic glycolysis to oxidative metabolism and lipogenesis. However, the metabolic landscape of human prostate cancer remains unclear.

To expand our understanding of prostate cancer metabolism, we turn to the serially transplantable prostate cancer patient-derived xenografts (PDXs) representing different stages of human prostate cancer (i.e., benign, localised, and metastatic). We performed ex vivo radiometric assays on precision-cut PDXs slices measuring the utilisation of 14C labelled substrates. The oxidation of glucose, glutamine, and fatty acids was variably upregulated in both localised and metastatic PDXs compared to benign PDXs, while lactate oxidation remained unchanged. Moreover, de novo lipogenesis and storage of extracellular-derived fatty acids into complex lipids, especially phospholipids and triacylglycerols, were also increased in malignant PDXs.

To gain further insights into the sites of metabolic regulation in prostate cancer, we subsequently performed ex vivo 13C stable isotope labelling of glucose, glutamine, palmitate, and lactate on the PDXs slices. The higher incorporation of all the labelled substrates into TCA cycle intermediates was observed in malignant PDXs, indicating increased substrate utilisation as observed in 14C assays. Glucose labelling showed higher conversion of glucose to lactate in benign PDXs, a stepwise increase of serine and glycine biosynthesis in benign, localised, and metastatic PDXs, and increased pyruvate-alanine cycling and PDH activity in malignant PDXs. Glutamine labelling highlighted the increase of reductive carboxylation of glutamine in malignant PDXs. These findings demonstrate that prostate cancer, irrespective of disease stage, can effectively utilise all metabolic substrates for energy production and biomass production, albeit with marked variation across donor tissues, and that individual tissues display unique metabolic capabilities.