Abstract B053: Lipid metabolism and lipidomics of ovarian clear cell carcinoma: a comprehensive analysis

Abstract Ovarian clear cell carcinoma (OCCC) is a chemoresistant subtype of ovarian cancer accounting for 5-12% of all epithelial ovarian cancer cases. Lipid metabolism has been reported to be involved in platinum resistance and resistance to ferroptosis induction in various cancer types. However, the metabolomic and lipidomic landscape of OCCC has not been characterized. To explore the metabolic processes driving the aggressive nature of advanced OCCC, we carried out global metabolomic and lipidomic profiling on 64 early and advanced ovarian cancer samples, including tumors with corresponding metastases. Snap frozen tissue from 29 OCCC, 22 high-grade serous carcinoma (HGSOC), and 13 endometrioid ovarian carcinoma (EnOC) cases were included. Hydrophilic interaction liquid chromatography (HILIC) -mass spectrometry was performed to quantify the relative steady-state level of 318 unique metabolites. Principal component analysis (PCA) showed a distinct separation between OCCC and HGSOC/EnOC samples, mainly driven by short and medium chain acylcarnitine and hydroxylated acylcarnitine esters that were significantly more abundant in OCCC. Acylcarnitines are intermediaries of fatty acid beta-oxidation (FAO), and their enrichment in OCCC patient samples might indicate a difference in fatty acid utilization and lipid metabolism compared to OCCC and HGSOC/EnOC. FAO has been linked to redox homeostasis in cancer cells, acting as a protective factor against lipid peroxidation through selective depletion of certain lipid species. To explore whether deeper lipidomic changes in OCCC accompany increased acylcarnitine production, we performed global complex lipid detection on 7 OCCCs and 3 HGSOC tissue samples using reverse phase liquid chromatography and mass spectrometry. Six-hundred and fifty-seven unique lipid species were successfully identified. A comparison of lipid class abundances between OCCC and HGSOC uncovered increased levels of medium chain acylcarnitines in OCCC, corroborating the HILIC findings. Moreover, the levels of cholesterol esters and ceramides with polyunsaturated fatty acid chains were also more abundant in OCCC. Conversely, choline plasmalogens, a lipid class known to induce lipid peroxidation and ferroptosis cell death exhibited significantly lower abundance in OCCC. Additionally, saturated ethanolamine plasmalogens and ceramides containing saturated fatty acids were decreased in OCCC. In summary, our study reports significant differences in the lipid metabolism of OCCC compared to other major ovarian cancer subtypes. The observed decrease in peroxidation-prone lipid species might indicate the involvement of FAO in OCCC’s redox homeostasis and highlights FAO as a potential novel mechanism of platinum resistance in OCCC. Ongoing studies, presented at the meeting include the metabolomic and lipidomic profiling of a large panel of ovarian cancer cell lines to identify those that best model patient sample metabolism. These models will subsequently be used for in vitro and in vivo studies to evaluate FAO as a potential therapeutic target in OCCC. Citation Format: Agnes J. Bilecz, Roya AminiTabrizi, Hardik Shah, Ernst Lengyel. Lipid metabolism and lipidomics of ovarian clear cell carcinoma: a comprehensive analysis abstract. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84 (5 Suppl₂): Abstract nr B053.