Ovarian cancer (OC) is the deadliest gynecological disease in women, with high-grade serous ovarian cancer (HGSC) being its most common and lethal subtype. This disease accounts for 75% of OC cases and has a five-year survival rate of only 32%, mainly due to diagnoses at an advanced stage. Inheriting a pathogenic BRCA1 or 2 mutation significantly increases the risk of developing HGSC. However, the early molecular processes that lead to this deadly subtype remain poorly understood. The ovarian hormone progesterone (P4) has been shown to induce metastatic HGSC in Dicer1-Pten double-knockout (DKO) mice, an animal model that develops this specific type of OC with molecular, histological, and clinical features similar to those of BRCA1/2 mutation carriers. To explore P4-induced metabolic changes before and after the onset of HGSC, we analyzed serum samples from DKO mice treated with P4 or mifepristone, an inhibitor of P4 signaling, at premalignant and early tumor stages. These samples underwent both targeted and non-targeted metabolomic analysis using ultra-high performance liquid chromatography-mass spectrometry. The non-targeted data revealed significant trends among various phospholipid classes, phosphatidylcholines, sphingomyelins, and triacylglycerols, in early-stage HGSC. Additionally, two metabolites previously linked to OC, lysophosphatidylethanolamine (18:1) and tetrahydrocortisone, were significantly elevated at the premalignant stage of HGSC development. Conversely, at this same stage, the targeted dataset showed notable increases in estrogens and glucocorticoids, while higher corticosterone levels were detected as HGSC began to develop. Overall, this study highlights the disruption of specific metabolites, phospholipid classes, and steroid hormones, in relation to HGSC tumor development under P4 treatment, suggesting their potential roles in OC development.
Schwiebert et al. (Mon,) studied this question.