Deep Metabolomics of a High-Grade Serous Ovarian Cancer Triple-Knockout Mouse Model.

Abstract

High-grade serous carcinoma (HGSC) is the most common and deadliest ovarian cancer (OC) type, accounting for 70-80% of OC deaths. This high mortality is largely due to late diagnosis. Early detection is thus crucial to reduce mortality, yet the tumor pathogenesis of HGSC remains poorly understood, making early detection exceedingly difficult. Faithfully and reliably representing the clinical nature of human HGSC, a recently developed triple-knockout (TKO) mouse model offers a unique opportunity to examine the entire disease spectrum of HGSC. Metabolic alterations were investigated by applying ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) to serum samples collected from these mice at premalignant, early, and advanced stages of HGSC. This comprehensive analysis revealed a panel of 29 serum metabolites that distinguished mice with HGSC from controls and mice with uterine tumors with over 95% accuracy. Meanwhile, our panel could further distinguish early-stage HGSC from controls with 100% accuracy and from advanced-stage HGSC with over 90% accuracy. Important identified metabolites included phospholipids, sphingomyelins, sterols, N-acyltaurine, oligopeptides, bilirubin, 2(3)-hydroxysebacic acids, uridine, N-acetylneuraminic acid, and pyrazine derivatives. Overall, our study provides insights into dysregulated metabolism associated with HGSC development and progression, and serves as a useful guide toward early detection.