Metabolic adaptation in epithelial ovarian cancer metastasis.

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  • Additional Information
    • Source:
      Publisher: Elsevier Country of Publication: Netherlands NLM ID: 101731730 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-260X (Electronic) Linking ISSN: 09254439 NLM ISO Abbreviation: Biochim Biophys Acta Mol Basis Dis Subsets: MEDLINE
    • Publication Information:
      Original Publication: Amsterdam : Elsevier
    • Subject Terms:
      Carcinoma, Ovarian Epithelial*/metabolism ; Carcinoma, Ovarian Epithelial*/pathology ; Spheroids, Cellular*/metabolism ; Spheroids, Cellular*/pathology ; Ovarian Neoplasms*/pathology ; Ovarian Neoplasms*/metabolism ; Citric Acid Cycle* ; Mitochondria*/metabolism ; Mitochondria*/pathology ; Neoplasm Metastasis*; Humans ; Female ; Cell Line, Tumor ; Glutamine/metabolism ; Energy Metabolism ; Metabolomics ; Glucose/metabolism
    • Abstract:
      Epithelial ovarian cancer (EOC) is highly lethal due to its unique metastatic characteristics. EOC spheroids enter a non-proliferative state, with hypoxic cores and reduced oncogenic signaling, all of which contribute to tumour dormancy during metastasis. We investigated the metabolomic states of EOC cells progressing through the three steps to metastasis. Metabolomes of adherent, spheroid, and re-adherent cells were validated by isotopic metabolic flux analysis and mitochondrial functional assays to identify metabolic pathways that were previously unknown to promote EOC metastasis. Although spheroids were thought to exist in a dormant state, metabolomic analysis revealed an unexpected upregulation of energy production pathways in spheroids, accompanied by increased abundance of tricarboxylic acid (TCA) cycle and electron transport chain proteins. Tracing of 13 C-labelled glucose and glutamine showed increased pyruvate carboxylation and decreased glutamine anaplerosis in spheroids. Increased reductive carboxylation suggests spheroids adjust redox homeostasis by shuttling cytosolic NADPH into mitochondria via isocitrate dehydrogenase. Indeed, we observed spheroids have increased respiratory capacity and mitochondrial ATP production. Relative to adherent cells, spheroids reduced serine consumption and metabolism, processes which were reversed upon spheroid re-adherence. The data reveal a distinct metabolism in EOC spheroids that enhances energy production by the mitochondria while maintaining a dormant state with respect to growth and proliferation. The findings advance our understanding of EOC metastasis and identify the TCA cycle and mitochondrional activity as novel targets to disrupt EOC metastasis, providing new approaches to treat advanced disease.
      Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
      (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
    • Contributed Indexing:
      Keywords: Anaplerosis; Metabolomics; Metastasis; Ovarian cancer; Oxidative phosphorylation; Serine; Spheroid; Tricarboxylic acid (TCA) cycle; electron transport chain
    • Accession Number:
      0RH81L854J (Glutamine)
      IY9XDZ35W2 (Glucose)
    • Publication Date:
      Date Created: 20240620 Date Completed: 20240816 Latest Revision: 20240910
    • Publication Date:
      20240911
    • Accession Number:
      10.1016/j.bbadis.2024.167312
    • Accession Number:
      38901649