Thesis
Untargeted metabolomics and proteomics application of mass spectrometry: from biomarker identification within cells to their spatial localization on tissues
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2022
- Thesis identifier
- T16537
- Person Identifier (Local)
- 201972578
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- Metabolomics is the newest omics science which studies the chemical changes of small molecules (metabolites) within cells and tissues of a living organism. Thanks to the implementation of liquid chromatography-mass spectrometry (LC-MS) and mass spectrometry imaging (MSI) analytical technologies, and the integration of multiple omics tools, metabolomics provides insight into the mechanisms underlying physiological and pathological conditions including ageing and cancer. Time-dependent accumulation of DNA damage has been observed during senescence, the state of cell cycle arrest and resistance to death which has been recognised as a driver of the ageing process. Similarly, genomic instability can initiate cancer and influence the overall prognosis of affected patients. Metabolomics has shown that metabolic reprogramming is another key characteristic of both ageing and cancer, necessary to sustain their survival in adverse conditions. Genomic instability and metabolic reprogramming contribute to the highly heterogeneous and dynamic phenotype of ageing and cancer, therefore predisposing patients to inferior clinical outcomes and resistance to treatments. Due to their heterogeneous and dynamic nature, isolating and effectively analysing the different phenotypes of both ageing and cancer is still a challenge. Owing to the implementation of mass spectrometry and its combination with microscopy technologies it is now possible to identify and spatially localise the distribution of new reliable and specific biomarkers for each individual phenotype. In this thesis, molecular assays coupled to mass spectrometry-based global metabolomics and proteomics techniques were employed to examine the changes occurring during cellular senescence upon induction of DNA damage, brain ageing in mice, and different breast cancer subtypes in response to DDR inhibition. The results presented show that at the cellular level senescence can be induced through replication stress, irradiation and DNA damage-inducing chemicals (hydroxyurea and etoposide), which share similar molecular features (growth arrest, flattened shape, expression of ß-galactosidase, DNA damage foci and cell cycle alteration), but different intra and extracellular metabolic components specific for each phenotype. At the tissue level, integration of global metabolomics and proteomics analysis allowed to design a putative metabolic map of the changes in the metabolites and proteins that were altered in the aged brain of mice. Moreover, the employment of mass spectrometry imaging (MSI) enabled the spatial localization of metabolites within specific regions of the brain. Finally, changes in cellular metabolism (glutamine and lipids metabolism) were observed in different breast cancer sub-phenotypes in response to DDR inhibition through Olaparib treatment. Overall, this thesis presents metabolomics – combined with molecular, proteomics studies and the high-resolution spatial determination of metabolites – as a powerful tool to reveal novel therapeutic targets for the treatment of ageing and age-related diseases (including cancer) and to comprehensively stratify different phenotypes relative to their tissue localization and based on their altered genetic alterations. When transferred into clinical diagnostics, this approach has future potential design personalised therapeutic approaches.
- Advisor / supervisor
- Rattray, Zahra
- Rattray, Nicholas J. W.
- Resource Type
- DOI
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