Quantifying mitochondria substrate utilisation in a heterogenous cancer metabolism landscape

Abstract

Cancer metabolism is characterised by dynamic substrate usage to meet bioenergetic and synthetic demands required to support tumour progression. The tricarboxylic acid (TCA) cycle is a central hub of many nutrients to fuel the electron transport chain and energy production, and generate signalling molecules and precursors for biomass synthesis. Projects within this thesis set out to comprehensively define the relationships of metabolic substrates within the mitochondria and identify common metabolic phenotypes amongst different cancer types.

In study 1, a ratio-metric metabolome analysis was performed on a panel of cancer cells from different lineages. This approach identified subsets of cancer cells that utilised glucose and glutamine differently by pathways converging at the TCA cycle. The insights from this project provide evidence to support that subsets of cancer cells are more sensitive to central carbon metabolism targeting therapeutics, irrespective of tissue lineage. In study 2, a parallel tracing strategy was performed in prostate cancer cells and discovered that extracellular long chain fatty acids (LCFAs) were minor carbon sources to the TCA cycle, compared to glucose and glutamine. This study also showed that exogenous LCFAs are incorporated into cardiolipins and that this was, in part, regulated at the mitochondrial entry of fatty acids (FAs). Study 3 expanded the observations of study 2 and found LCFAs were again minor carbon sources to the TCA cycle in a panel of cancer cells, irrespective of FA oxidation activity.

This thesis provides new insights into how cancer cells from different tissue lineages metabolise exogenous substrates within the mitochondria. Overall, the studies in this thesis identified common metabolic signatures within subsets of cancer cells that could provide new approaches to drug repurposing strategies beyond the scope of a particular cancer type.