Abstract 4172: Carnitine metabolism regulates ovarian cancer metastasis

Abstract Ovarian cancer (OvCa), the most lethal gynecological malignancy, is often detected late when the cancer cells have metastasized throughout the peritoneal cavity. OvCa cells are readily shed into the abdominal cavity from the ovary or the fallopian tube and are disseminated throughout the peritoneal cavity via the peritoneal or ascetic fluid. Therefore, ascites function as a liquid tumor microenvironment intermediary between primary tumor and metastasis. It is unclear if the ascites is a mere vehicle for disseminating cancer cells or if it alters the metabolic machinery of OvCa cells to increase their metastatic capacity. Here, we performed systematic multi-site metabolomic analyses to characterize the metabolic milieu of ascites and identified the mechanisms that augment the metastatic capacity of OvCa cells. We analyzed patient-matched samples (comprised of primary, metastatic omental tumors, ascites, and plasma) collected from a cohort of 25 high-grade serous ovarian cancer patients using liquid chromatography-mass spectrometry. By performing multidimensional scaling, we show that each sample site has a characteristic metabolic profile. The metabolome of the ascites is unique, and a higher abundance of acylcarnitines distinguishes its metabolome from patient-matched tumor and plasma. Conjugation of fatty acids to carnitine (generating acylcarnitines) aids in transfer of fatty acids across the mitochondrial membrane for their oxidation and subsequent ATP generation. We found that ascites-driven growth of OvCa cells correlates with methionine uptake and accumulation of N6-trimethyl-L-lysine (a key metabolite in the biosynthesis of carnitine). We also observed increased levels of acylcarnitines in metastatic tumors from the omentum compared to primary ovarian/fallopian tube tumors. Therefore, increased carnitine synthesis is a metabolic phenotype of OvCa cells growing in ascites and is associated with progression through the metastatic cascade. Gamma-butyrobetaine hydroxylase 1 and 2 (BBOX1 and BBOX2), are enzymes that regulate the rate-limiting steps of carnitine synthesis. Stable knockdown of BBOX1 and BBOX2 reduced the growth rate, and migratory and invasive capacities of OvCa cells in vitro. Colonization of the omentum (a visceral adipose tissue covering the bowel) marks an essential step in OvCa progression. We and others have shown that heightened fatty acid oxidation capacity in cancer cells aids in omental metastasis. We now show that increased carnitine biosynthesis in the OvCa cells precedes omental colonization and is a potential metabolic vulnerability. Citation Format: Medine Tasdemir, Shree Bose, Jason Locasale, Ernst Lengyel, Abir Mukherjee. Carnitine metabolism regulates ovarian cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4172.