Understanding the metabolic transformation of cancer cells

Christian Frezza
Understanding the metabolic transformation of cancer cells

Cancer cannot be defined as a single disease, but rather a collection of diseases with distinct histopathological and genetic features. Nevertheless, all cancers share many common traits, among which unrestrained cellular proliferation is the most apparent.

The cellular signals that drive chronic proliferation have been extensively studied in the past decades, revealing a set of deregulated oncogenes and tumour suppressors. However, in order to sustain cell growth and proliferation cancer cells must undergo a complex metabolic transformation, whereby several metabolic pathways converge to provide the growing cell with all the nutrients required for this process. Indeed, it is now emerging that several oncogenes and tumour suppressors, besides their role in cell signalling, control the activity of different metabolic pathways to support the metabolic transformation of a cancer cell.

The connection between cancer and metabolism has become even stronger after the discovery that some key metabolic enzymes such as Succinate Dehydrogenase, Fumarate Hydratase, Isocitrate Dehydrogenase and Phosphoglycerate Dehydrogenase, if mutated, could lead to different forms of cancer. These findings suggest that altered metabolism is not only a required event to support proliferation but in some instances can be the leading cause of cancer, tracing back to the initial hypothesis of Otto Warburg, a pioneer in the field of cancer metabolism.

By using a combination of biochemistry, metabolomics, and systems biology we will investigate the role of altered metabolism in cancer with the aim to understand how metabolic transformation regulates the process of tumorigenesis. Our aim is to exploit these findings to establish novel therapeutic strategies and diagnostic tools for cancer.

Schematic representation of the metabolic transformation of a cancer cell.

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Several oncogenes and tumour suppressors orchestrate profound changes in cellular metabolism. For instance, AKT, Myc and HIF activate different glycolytic enzymes supporting aerobic glycolysis (red arrows). On the other side, p53 negatively regulate the glycolytic flux (blue line), diverting carbons to the pentose phosphate pathway to generate ribose, required for nucleotides biosynthesis and DNA repair. The amplification of the glycolytic enzyme Phosphoglycerate Dehydrogenase (PHGDH) was found in several cancers and biochemical investigations revealed that the activation of serine biosynthesis supports cellular proliferation. p53 and HIF regulate also oxidative phosphorylation (OXPHOS) coupling changes in glycolysis to changes in mitochondrial activity (red arrows). The tricarboxylic acid cycle (TCA cycle) is a central metabolic hub in the mitochondria and generates a plethora of metabolic intermediates required for anabolic reactions, such as lipid biosynthesis. Mutations in Fumarate Hydratase (FH), Succinate Dehydrogenase (SDH) and Isocitrate Dehydrogenase (IDH) are found in different types of hereditary and sporadic tumours. Mutations in IDH1 or IDH2 lead the formation of a poorly characterised metabolite, 2 hydroxyglutarate whereas mutations in SDH and FH lead to the accumulation of succinate and fumarate respectively. The oncogenic potential of these metabolites is under intense investigation and granted them the label of “oncometabolites”. Glutamine metabolism is another important aspect of cancer metabolism and it is governed by several genes such as p53 and Myc (red arrows).

Contact

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Selected Publications

Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase. Frezza C, Zheng L, Folger O, Rajagopalan KN, MacKenzie ED, Jerby L, Micaroni
M, Chaneton B, Adam J, Hedley A, Kalna G, Tomlinson IP, Pollard PJ, Watson DG,
Deberardinis RJ, Shlomi T, Ruppin E, Gottlieb E. Nature. 2011 Aug 17;477(7363):225-8.

Metabolic profiling of hypoxic cells revealed a catabolic signature required for cell survival. Frezza C, Zheng L, Tennant DA, Papkovsky DB, Hedley BA, Kalna G, Watson DG,
Gottlieb E. PLoS One. 2011;6(9):e24411.

The music of lipids: How lipid composition orchestrates cellular behaviour. Schug ZT, Frezza C, Galbraith LC, Gottlieb E. Acta Oncol. 2012 Mar;51(3):301-10.

Predicting selective drug targets in cancer through metabolic networks. Folger O, Jerby L, Frezza C, Gottlieb E, Ruppin E, Shlomi T. Mol Syst Biol. 2011 Jun 21;7:501. Erratum in: Mol Syst Biol. 2011;7. doi:10.1038/msb.2011.51.

Inborn and acquired metabolic defects in cancer. Frezza C, Pollard PJ, Gottlieb E.J Mol Med (Berl). 2011 Mar;89(3):213-20.

OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion.Frezza C, Cipolat S, Martins de Brito O, Micaroni M, Beznoussenko GV, Rudka T, Bartoli D, Polishuck RS, Danial NN, De Strooper B, Scorrano L. Cell. 2006 Jul 14;126(1):177-89.

To undertake world leading research into cancer cell biology that can be translated into clinical practice to improve the diagnosis and treatment of cancers.