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 chromatographymass 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.

Dysregulated Metabolites Serve as Novel Biomarkers for Metabolic Diseases Caused by E-Cigarette Vaping and Cigarette Smoking

“…Blood samples were spin down at room temperature for 5 min, 1000 rpm, then transfer the plasma into a new tube and stored at −80 • C [60] for UPLC-MS analysis.…”

“…UPLC-MS analyses were performed at the Mass Spectrometry Core Facility at Georgia Institute of Technology according to previously described protocols [60].…”

Targeting progesterone signaling prevents metastatic ovarian cancer

“…7C), suggesting a presumed role of progesterone in immune suppression and inflammation (61,62). Additionally, as significant metabolome changes are evident during the development and progression of HGSC (63), progesterone may also elicit metabolomic alterations specific to HGSC development. Crucially, known as "BRCAness," tumors wild type for BRCA1/2 can harbor molecular features similar to those in tumors from BRCA-mutation carriers (42).…”

In vivo modeling of metastatic human high-grade serous ovarian cancer in mice

“…development and progression in TKO model, our recent study has identified a panel of 29 serum metabolites that can distinguish early-stage HGSC from normal controls and also from advanced-stage HGSC with high accuracy, thus offering useful guidance on early detection of ovarian cancer [59].…”