Dokument-ID Dokumenttyp Verfasser/Autoren Herausgeber Haupttitel Abstract Auflage Verlagsort Verlag Erscheinungsjahr Seitenzahl Schriftenreihe Titel Schriftenreihe Bandzahl ISBN Quelle der Hochschulschrift Konferenzname Quelle:Titel Quelle:Jahrgang Quelle:Heftnummer Quelle:Erste Seite Quelle:Letzte Seite URN DOI Abteilungen OPUS4-18154 Dissertation Kaymak, Irem Identification of metabolic liabilities in 3D models of cancer Inefficient vascularisation of solid tumours leads to the formation of oxygen and nutrient gradients. In order to mimic this specific feature of the tumour microenvironment, a multicellular tumour spheroid (SPH) culture system was used. These experiments were implemented in p53 isogenic colon cancer cell lines (HCT116 p53 +/+ and HCT116 p53-/-) since Tp53 has important regulatory functions in tumour metabolism. First, the characteristics of the cells cultured as monolayers and as spheroids were investigated by using RNA sequencing and metabolomics to compare gene expression and metabolic features of cells grown in different conditions. This analysis showed that certain features of gene expression found in tumours are also present in spheroids but not in monolayer cultures, including reduced proliferation and induction of hypoxia related genes. Moreover, comparison between the different genotypes revealed that the expression of genes involved in cholesterol homeostasis is induced in p53 deficient cells compared to p53 wild type cells and this difference was only detected in spheroids and tumour samples but not in monolayer cultures. In addition, it was established that loss of p53 leads to the induction of enzymes of the mevalonate pathway via activation of the transcription factor SREBP2, resulting in a metabolic rewiring that supports the generation of ubiquinone (coenzyme Q10). An adequate supply of ubiquinone was essential to support mitochondrial electron transport and pyrimidine biosynthesis in p53 deficient cancer cells under conditions of metabolic stress. Moreover, inhibition of the mevalonate pathway using statins selectively induced oxidative stress and apoptosis in p53 deficient colon cancer cells exposed to oxygen and nutrient deprivation. This was caused by ubiquinone being required for electron transfer by dihydroorotate dehydrogenase, an essential enzyme of the pyrimidine nucleotide biosynthesis pathway. Supplementation with exogenous nucleosides relieved the demand for electron transfer and restored viability of p53 deficient cancer cells under metabolic stress. Moreover, the mevalonate pathway was also essential for the synthesis of ubiquinone for nucleotide biosynthesis to support growth of intestinal tumour organoids. Together, these findings highlight the importance of the mevalonate pathway in cancer cells and provide molecular evidence for an enhanced sensitivity towards the inhibition of mitochondrial electron transfer in tumour-like metabolic environments. 2019 urn:nbn:de:bvb:20-opus-181544 10.25972/OPUS-18154 Graduate School of Life Sciences OPUS4-7275 Teil eines Buches Anders, F.; Scholl, E.; Schartl, Manfred Xiphophorus als Modell in der Krebsforschung No abstract available. 1979 urn:nbn:de:bvb:20-opus-72752 Theodor-Boveri-Institut für Biowissenschaften OPUS4-6356 Dissertation Zeeshan, Ahmed Bioinformatics Software for Metabolic and Health Care Data Management Computer Science approaches (software, database, management systems) are powerful tools to boost research. Here they are applied to metabolic modelling in infections as well as health care management. Starting from a comparative analysis this thesis shows own steps and examples towards improvement in metabolic modelling software and health data management. In section 2, new experimental data on metabolites and enzymes induce high interest in metabolic modelling including metabolic flux calculations. Data analysis of metabolites, calculation of metabolic fluxes, pathways and their condition-specific strengths is now possible by an advantageous combination of specific software. How can available software for metabolic modelling be improved from a computational point of view? A number of available and well established software solutions are first discussed individually. This includes information on software origin, capabilities, development and used methodology. Performance information is obtained for the compared software using provided example data sets. A feature based comparison shows limitations and advantages of the compared software for specific tasks in metabolic modeling. Often found limitations include third party software dependence, no comprehensive database management and no standard format for data input and output. Graphical visualization can be improved for complex data visualization and at the web based graphical interface. Other areas for development are platform independency, product line architecture, data standardization, open source movement and new methodologies. The comparison shows clearly space for further software application development including steps towards an optimal user friendly graphical user interface, platform independence, database management system and third party independence especially in the case of desktop applications. The found limitations are not limited to the software compared and are of course also actively tackled in some of the most recent developments. Other improvements should aim at generality and standard data input formats, improved visualization of not only the input data set but also analyzed results. We hope, with the implementation of these suggestions, metabolic software applications will become more professional, cheap, reliable and attractive for the user. Nevertheless, keeping these inherent limitations in mind, we are confident that the tools compared can be recommended for metabolic modeling for instance to model metabolic fluxes in bacteria or metabolic data analysis and studies in infection biology. ... 2012 urn:nbn:de:bvb:20-opus-73926 Theodor-Boveri-Institut für Biowissenschaften