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

SIMPLE SUMMARY: The underlying mechanisms associated with ovarian cancer progression remain largely unknown, making it one of the most lethal cancers. To understand the disease pathogenesis, our study involved longitudinal serum metabolomics profiling of a triple-mutant mouse model of ovarian cancer that captured the dynamic metabolic response from disease onset until mouse death. These experiments were complemented with spatial lipidomic profiling of the entire reproductive system of the triple-mutant mice, enabling us to visualize the tissue heterogeneity and lipid alterations within tumors. A combined longitudinal and spatial map of metabolomic alterations associated with ovarian cancer progression is presented, serving as a comprehensive guide towards understanding the disease origin and progression. ABSTRACT: 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.