Space- and Time-Resolved Metabolomics of a High-Grade Serous Ovarian Cancer Mouse Model

Cancers

Olga Kim¹  Sylvia R. Yun¹  Jaeyeon Kim¹  Andro Botros¹  Eun Young Park¹  Samuel G. Moore²  Xin Ma²  David A. Gaul²  Facundo M. Fernández²  Samyukta Sah² 

[1] Departments of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA;School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332, USA;

关键词: high-grade serous ovarian cancer;    metabolomics;    mass spectrometry;    imaging;    biomarkers;   

DOI  :  10.3390/cancers14092262

来源: DOAJ

【 摘 要 】

The dismally low survival rate of ovarian cancer patients diagnosed with high-grade serous carcinoma (HGSC) emphasizes the lack of effective screening strategies. One major obstacle is the limited knowledge of the underlying mechanisms of HGSC pathogenesis at very early stages. Here, we present the first 10-month time-resolved serum metabolic profile of a triple mutant (TKO) HGSC mouse model, along with the spatial lipidome profile of its entire reproductive system. A high-coverage liquid chromatography mass spectrometry-based metabolomics approach was applied to longitudinally collected serum samples from both TKO (n = 15) and TKO control mice (n = 15), tracking metabolome and lipidome changes from premalignant stages to tumor initiation, early stages, and advanced stages until mouse death. Time-resolved analysis showed specific temporal trends for 17 lipid classes, amino acids, and TCA cycle metabolites, associated with HGSC progression. Spatial lipid distributions within the reproductive system were also mapped via ultrahigh-resolution matrix-assisted laser desorption/ionization (MALDI) mass spectrometry and compared with serum lipid profiles for various lipid classes. Altogether, our results show that the remodeling of lipid and fatty acid metabolism, amino acid biosynthesis, TCA cycle and ovarian steroidogenesis are critical components of HGSC onset and development. These metabolic alterations are accompanied by changes in energy metabolism, mitochondrial and peroxisomal function, redox homeostasis, and inflammatory response, collectively supporting tumorigenesis.

【 授权许可】

Unknown