Background and Elucidating the Metabolic Pathway
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. To better understand the disease pathogenesis, we are investigating the time-resolved serum metabolic profile of two mouse models of HGSC (1) a double-knockout (DKO) mice (Dicer1 flox/flox Pten flox/flox Amhr2 cre/+)1 by inactivating the Dicer1 and Pten genes, and (2) a triple-mutant (TKO) mice (p53 LSL-R172H/+ Dicer1 flox/flox Pten flox/flox Amhr2 cre/+)2 by adding a p53 mutation (R172H), which is equivalent to human p53-R175H mutant, one of the frequent p53 mutations found in human OC. Early metabolome changes associated with HGSC progression are investigated via high coverage untargeted liquid chromatography – mass spectrometry coupled with machine learning methods, and targeted microchip capillary electrophoresis metabolomics approaches. Specifically, ultrahigh performance liquid chromatography-mass spectrometry (UHPLC-MS) is used for profiling sequentially collected serum samples from the animal models starting from 8 weeks of age tracking metabolome and lipidome changes from premalignant stages to tumor initiation, early stages, and advanced stages until mouse death. Unlike conventional single time-point studies, which do not fully capture the dynamic metabolic response associated with disease development, time-resolved metabolic profiling allows mapping metabolite alterations as the HGSC progresses. Time-course metabolic changes show specific temporal trends for lipid classes, amino acids, and TCA cycle metabolites and indicate 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.
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