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MELANOMA ORIGINATES from the pigment-producing cells in the skin, the melanocytes. The deadliest form of skin cancer, it readily spreads to other parts of the body and is highly resistant to chemotherapy. Dr Fabian Filipp is Assistant Professor of Systems Biology and Cancer Metabolism at the Health Sciences Research Institute of the University of California, Merced. His studies centre on the molecular processes that govern cellular metabolism, with a view to finding ways of selectively killing cancer cells and stopping their proliferation and spread. Filipp combines cancer pathology with biophysical approaches. His systems biology approach to cancer reveals the complexity and interconnectedness of the networks of genes, proteins and other cellular molecules that underpin biological function, and hence dysfunction.
The driving force is to target cancer metabolism: “It is incredible being able to visualise how a binding pocket frames its ligand, or to model atomic transitions during an enzymatic conversion. If the structure of a binding pocket helps design inhibitors, it’s an unbeatable team,” Filipp elaborates.
Prior investigations into the metabolic mechanisms of melanoma have been scant. Filipp is thus exploring the structural biology of lipogenesis in the cancer’s progression with the aim of translating the outcomes into clinical research. His team develops nuclear magnetic resonance imaging-based diagnostic tools to examine cancer progression and metabolic disease and the responses of these diseases to nutrients and drugs; and they also designs computational methods for modelling dynamic networks of genomic, transcriptomic, proteomic, metabolomic and fluxomic data.
Normal cell growth and function relies on access to sufficient oxygen and nutrients, such as glucose and glutamine. Cancer cells grow and proliferate more rapidly than normal cells, therefore consuming elevated quantities of nutrients, Dr Otto Warburg noted that cancer cells rely heavily on glycolysis, whereas normal cells take advantage of the more energy-efficient mitochondrial oxidative phosphorylation to generate energy. Filipp points out that, because of this, “a common misperception is that tumours manifesting aerobic glycolysis do so because mitochondrial oxidative phosphorylation is somehow impaired”.
Because melanoma thrives even in the low oxygen conditions of the skin, Filipp and his collaborators examined melanoma cells using metabolic tracers. This demonstrated that the fundamental citric acid cycle is completely rewired when melanoma cells are deprived of oxygen. The cycle is mostly disconnected from glycolysis; its flux runs in reverse, using glutamine rather than glucose as a source of carbon, and producing fatty acids from glutamine and primarily lactate from glucose; the process is coordinated by isocitrate dehyrdogenase enzymes.
The researchers then addressed the question of how melanoma cells manufacture large quantities of molecular building blocks by examining their metabolic flux. Using stable isotope tracing, bioanalytical spectroscopy and metabolic network modelling, they showed that the citric acid cycle in the mitochondria of melanoma cancer cells is not only intact but actually functions extremely well in biosynthesis and processing glutamine into energy, and that this happens independently of glycolysis: “This phenomenon ‘beyond the Warburg effect’, as we term it, is both a hallmark of malignant transformation and a potential therapeutic target,” Filipp asserts.
Recently, the group explored the cancerous form of pyruvate kinase, PKM2. PKM2 differs from the normal form of pyruvate kinase, PKM1, in less than S per cent of its amino acids, and is expressed in most cancerous tumour cells. Using genomics, transcriptomics, proteomics, metabolomics and fluxomics, their studies revealed that pyruvate kinase is a rate-limiting glycolytic enzyme that converts phosphoenol pyruvate and adenosine diphosphate to pyruvate and ATP, thereby contributing to aerobic glycolysis, biomass production and lactate fermentation, Because of its versatile mechanisms of action and its ability to reinvent itself in response to changes in its environment PKM2 helps cancer cells to withstand perturbations and to maintain growth.
Filipp feels that PKM2 presents unprecedented opportunities for new therapies, because subtle changes to its structure could lead to a reversal of the global rewiring of the metabolism of cancer, as he concludes: “The master regulator PKM2 is in the centre of glycolytic action, since it is able to integrate signals at the gene, transcription, protein, metabolite and flux levels far away from the actual target”.
To design molecular tools for disease diagnosis and treatment in response to cancer progression, metabolic disease, nutrients and drugs.
National Institutes of Health National Cancer Institute (NIH NCI). F.V.F. is grateful for the support of grant CA154887 from the National Institutes of Health, National Cancer Institute.
European Molecular Biology Organization (EMBO)
DR FABIAN FILIPP undertook his undergraduate training in Biochemistry at the University of Regensburg, Germany. He received an MSc and Doctor of Science in Biophysics from the University of Heidelberg, Germany, and a PhD in Nuclear Magnetic Resonance (NMR) Spectroscopy from the European Molecular Biology Laboratory (EMBL), Heidelberg. He was awarded the accolade of EMBO Long Term Fellow in 2008 and the NIH NCI Fellow in 2010. Filipp’s research interests are in systems biology, melanoma progression, flux analysis, mass spectrometry, NMR spectroscopy, and cancer metabolism.