<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Uncovering functional metabolic pathways using metabolomics: case studies of mammalian nucleus and dormant cancer cells"^^ . "Beyond its fundamental role in fulfilling the nutritional and energetic needs of the cell, metabolism has emerged as an important component of cellular regulatory processes which are central to diverse biological phenomena, ranging from cell differentiation to cancer and longevity. These metabolic pleiotropic roles often converge on the crosstalk with gene expression regulation which is sensitive to the availability of specific metabolites utilized for chromatin and RNA chemical modifications. These required metabolites are often assumed to freely diffuse into the nuclear space, with their key biosynthetic pathways mainly assigned to function elsewhere. However, considering that the intracellular environment is a rather viscous space where the free diffusion between the different compartments could be restricted, a significant question arises of how the nucleus ensures a reliable supply of these essential metabolites, especially as it is often a reaction-diffusion scenario and not only diffusion. Along these lines, the aim of the current PhD thesis was to explore the hypothesis that the nucleus could harbor extended metabolic networks, and not only individual enzymatic steps, for local production of nuclear-relevant metabolites. To examine this, firstly, nuclear proteomics data and nuclear localization signal motif analysis were utilized to assess the potentiality of a nuclear presence of the corresponding metabolic enzymes. Next, by employing stable isotope [U-13C]-based metabolomics analysis in isolated nuclei, we tracked an operational activity. Proximity ligation mass spectrometry for selected enzymatic players allowed us to examine their proximity interactome further corroborating a nuclear subcellular topology. Cumulatively, our data provided multi-level evidence for a functional metabolic pathway operating in a mammalian nucleus. The identified pathway is made of parts of the TCA cycle with intermediates having key roles in chromatin and RNA modifications, reflecting thus the presence of a metabolic nuclear niche ensuring a stable supply of essential metabolites with nucleus-relevant functionalities.\r\nThe aforementioned crosstalk between metabolism and gene expression regulation highlights the importance of considering metabolic deregulations in pathophysiological conditions. Cancer metabolic alterations are a well-studied phenomenon. Yet, little is known for the metabolic physiology of residual cancer cells that survive treatment and contribute to cancer relapse. The current PhD thesis contributed to the characterization of the metabolic particularities of residual cancer cells derived from a mouse model of breast cancer. The analysis indicated that the residual cells, although phenotypically similar to their normal counterparts and despite the absence of oncogenes expression, preserved a tumorous metabolic memory with main characteristics of an enhanced glycolysis, deregulated TCA and urea cycle. Considering glycolysis’ central role, we next aimed at investigating the network-wide metabolic responses upon inhibition of two important facilitators of the pathway, namely lactate dehydrogenase A and the monocarboxylate transporters 1 and 2, involved in lactate generation and transportation, respectively, in cancer cell lines. The results revealed opposite changes in metabolite concentration pools in glycolysis and TCA cycle intermediates between the two inhibitors treatment, and an overall lower biosynthetic flux. Interesting metabolic nodes were identified that could potentially be therapeutically exploited.\r\nUncovering and understanding metabolic network activities in previously overlooked places, like the existence of a nuclear multistep metabolic network, or the perseverance in cancer regressed cells of a metabolic phenotype mnemonic to the tumorous state, can shed light on the hitherto unknown mechanisms of gene regulation and its interplay with the metabolic state of a cell."^^ . "2020" . . . . . . . "Eleni"^^ . "Kafkia"^^ . "Eleni Kafkia"^^ . . . . . . "Uncovering functional metabolic pathways using metabolomics: case studies of mammalian nucleus and dormant cancer cells (PDF)"^^ . . . "Kafkia_Eleni_PhD_thesis.pdf"^^ . . . "Uncovering functional metabolic pathways using metabolomics: case studies of mammalian nucleus and dormant cancer cells (Other)"^^ . . . . . . "indexcodes.txt"^^ . . "HTML Summary of #27032 \n\nUncovering functional metabolic pathways using metabolomics: case studies of mammalian nucleus and dormant cancer cells\n\n" . "text/html" . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . .