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Mass Spectrometry Imaging of Lipid Profiles in Disease
[Thesis]. Manchester, UK: The University of Manchester; 2017.
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Abstract
It is well established that lipids play an important role in diseases such as non-alcoholic fatty liver disease and cardiovascular diseases. However, in the past decade, it has come to light that lipids may be important in other diseases; particularly in cancer and neurological disorders. Here, lipid metabolism has been investigated using pre-clinical cancer models for melanoma, glioma, non-small-cell lung cancer and colorectal cancer. The role of lipids in the recovery post-stroke has also been studied. Mass spectrometry imaging offers an ideal tool to study lipids in tissue ex-vivo. Lipids ionise well in a number of mass spectrometry modalities, and hundreds of lipids can be imaged in one mass spectrometry imaging experiment. Furthermore, mass spectrometry imaging offers excellent spatial resolution. In this work, both MALDI-MS and DESI-MS have been used for mass spectrometry imaging.Tumour lipid heterogeneity has been a particular focus of this this project. Heterogeneity exists within tumours, as well as between tumours in the same patient; and this causes major problems for therapy. Owing to the untargeted nature, and high spatial resolution of mass spectrometry imaging, it is an excellent technique to study lipid heterogeneity. Adjacent sections (or in some cases the same section used for mass spectrometry imaging), were used for immunofluorescence and H&E staining. By comparing mass spectrometry images with staining techniques, biological reasons for lipid heterogeneity can be established. Here, a particular focus has been on hypoxia (low oxygen tensions), which is a key contributor to tumour heterogeneity, and is associated with aggressive cancers. Additionally, hypoxia is a feature of ischaemic stroke, and lipids in ischaemic stroke have also been investigated. PET is a non-invasive imaging technique which is able to image a radiolabelled molecule (tracer) in the body. Here, PET has been used as a complementary in-vivo technique to mass spectrometry imaging. The tracers [11C] acetate and [18F]-FTHA have been used to image fatty acid synthase and fatty acid uptake in tumours; both of which are hypothesised to be key in cancer progression. REIMS is a newly established mass spectrometry technique. It is ideal for analysing lipids in cells, as sample preparation is minimal. Here, approaches for cell pellet analysis have been tested, and used to detect lipids in cancer cell lines.