Unlocking metabolic regulation in leukaemic cancers for future treatment
Metabolic changes in cells are a major hallmark of cancer. Cellular metabolism is regulated by the expression or suppression of enzymes that control the production of energy and other essential building blocks for cells. These pathways are often rewired in cancer cells, although much remains unknown about the mechanisms involved. The EU-supported HaemMetabolome project focused mainly on acute myeloid leukaemia (AML), a blood cancer driven by a combination of mutations leading to a malignant transformation of cells. As these cancers are still very difficult to treat, with 5-year survival rates only around 15 % in Europe, better treatment options are urgently needed. The Marie Skłodowska-Curie Training Network provided specialist training for 10 Early Stage Researchers in disciplines linking cancer cell biology with key technologies involving bioinformatics, mathematical modelling and drug discovery.
Methodological breakthrough
As energy metabolism is linked to cellular control, being able to influence it would offer an opportunity to treat cancer. So HaemMetabolome investigated how energy metabolism is related to genetics and signal transduction in AML cells. To do so, the project used mass spectrometry (MS) and nuclear magnetic resonance (NMR) techniques to screen haematological cancer cell lines and primary patient samples for their metabolic phenotypes. They also performed gene-function analyses on key metabolic regulators. “We were the first to use NMR for in-depth metabolic analyses in cancer cell lines and primary cancer cells – an important methodological breakthrough,” says Ulrich Günther, project coordinator. HaemMetabolome investigated the small molecule chemicals of immature blast cells from AML patients. They compared these to the patient’s genes and all the proteins that can be expressed by a cell. “Prior to our study, little was known about the differences between healthy stem cells and AML cells. AML genetic mutations result in clear signalling differences, and so we suspected we would also identify metabolic differences,” explains Jan Schuringa, deputy coordinator and research lead. Energy metabolism produces adenosine triphosphate (ATP), a compound driving many cell processes. The project’s studies indicated that some subtypes of AML produce ATP from glucose, a process known as glycolysis, while others rely on enzymes oxidising nutrients. The team identified a key element which regulates this switch – important because inhibition of this switch impaired leukaemia development in a subset of cases. This was validated in laboratory tests, including in patient-derived xenograft immunodeficient mice. Another study examined the role of individual metabolites by screening cells in metabolite-depleted media, identifying the importance of specific amino acids. One student studied metabolic reprogramming in those connective tissue cells in contact with AML cells. They identified metabolites which provide AML cells with the nutrients necessary for their survival.
Therapeutic potential
The MS methods used kits such as Biocrates kits to measure metabolism and metabolic fluxes. They also developed data analysis software based on gas chromatography-mass spectrometry flux methods. Both are currently available to researchers. Information about the project’s new NMR methods for studying real-time metabolism has already been published, with other NMR labs already adopting the methods. “Revealing the range of AML metabolic reprogramming should help therapeutic targeting. Our metabolite depletion results, which identified a strong role for individual metabolites associated with enzymes, represent promising drug targets,” concludes Günther. As primary human cells were only used for a subset of the metabolic mechanisms revealed by the project, further corroborative work is needed.
Keywords
HaemMetabolome, blood, cancer, metabolism, genetics, metabolite, Nuclear Magnetic Resonance, energy, cells, Mass Spectrometry, leukaemia
