Abstract B037: WNT4-mediated metabolomic reprograming favors lipid utilization in ovarian clear cell carcinoma

Abstract Ovarian clear cell carcinoma (OCCC) is an aggressive, endometrial-derived subtype of ovarian cancer (OvCa) which affects young women. Late stage OCCC is resistant to chemotherapy and has the worst outcome compared to other OvCa subtypes. Compared to these subtypes, OCCC cells have a lower glycolytic capacity and altered lipid profile including increased acylcarnitine, a fatty acid oxidation intermediate, indicating that OCCC has a unique metabolic signature compared to other subtypes. In pursuit of risk factors that drive metabolic changes in OCCC, we have focused our studies on WNT4, which is an important protein for gynecologic development. In the WNT4 gene, there is a common single nucleotide polymorphism (SNP; rs3820282) in intron 1, a C>T transition that creates a binding site for nuclear receptor transcription factors, increasing WNT4 expression. The WNT4 variant is associated with an 11% increased overall risk of ovarian cancer (OvCa) and a 24% increased risk of ovarian clear cell carcinoma (OCCC). The WNT4 variant is most inherited in East Asian populations (up to 55% variant allele frequency), mirroring the high prevalence of OCCC in East Asian populations (15-25% of OvCa cases) compared to North America and Europe (5-10% of OvCa cases). Unlike other WNT proteins, we have shown that WNT4 localizes to mitochondria, using proximity-dependent biotinylation (BioID). In WNT4-variant OvCa, cells are dependent on WNT4 protein for mitochondrial function and proliferation. Using mass spectrometry-based metabolomics, we showed that knockdown of WNT4 in WNT4-variant lines increases fatty acid metabolites, indicating that these metabolites are used in the presence of WNT4. Functionally, this impacts proliferative capacity; while WNT4 knockdown has no effect on proliferation in Wild-Type OvCa lines, WNT4 knockdown in WNT4-variant OvCa lines decreases proliferation. Moreover, proliferation in WNT4-variant OCCC is uniquely dependent on lipid utilization. In Wild-Type lines, TOV21G and UPK10, there was no change in proliferation with lipid deprivation, however in WNT4-variant lines, OVTOKO and OVISE, there was a 10% and 70% reduction in proliferation, respectively. Additionally, in OVISE cells, WNT4 is regulated by lipid; lipid deprivation causes a 60% reduction in WNT4 expression. The WNT4 SNP rs3820282 creates a unique metabolomic profile in ovarian cancer, enhancing proliferative capacity through WNT4-dependent utilization of fatty acid metabolites, creating an opportunity for targeted OCCC therapeutics. Citation Format: Taylor M. Benson, Madeleine Shackleford, Sydney Robinson, Ritsuko Iwanaga, Benjamin Bitler, Matthew Sikora. WNT4-mediated metabolomic reprograming favors lipid utilization in ovarian clear cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr B037.