Department of Obstetrics & Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P.R. China.
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, People's Republic of China.
Theranostics. 2022 Apr 24;12(7):3534-3552. doi: 10.7150/thno.70194. eCollection 2022.
Malignant ascites in peritoneal metastases is a lipid-enriched microenvironment and is frequently involved in the poor prognosis of epithelial ovarian cancer (EOC). However, the detailed mechanisms underlying ovarian cancer (OvCa) cells dictating their lipid metabolic activities in promoting tumor progression remain elusive. The omental conditioned medium (OCM) was established to imitate the omental or ascites microenvironment. Mass spectrometry, RT-qPCR, IHC, and western blot assays were applied to evaluate human fatty acid desaturases expressions and activities. Pharmaceutical inhibition and genetic ablation of SCD1/FADS2 were performed to observe the oncogenic capacities. RNA sequencing, lipid peroxidation, cellular iron, ROS, and Mito-Stress assays were applied to examine ferroptosis. OvCa patient-derived organoid and mouse model of peritoneal metastases were used to evaluate the combined effect of SCD1/FADS2 inhibitors with cisplatin. We found that two critical fatty acid desaturases, stearoyl-CoA desaturase-1 (SCD1) and acyl-CoA 6-desaturase (FADS2), were aberrantly upregulated, accelerating lipid metabolic activities and tumor aggressiveness of ascites-derived OvCa cells. Lipidomic analysis revealed that the elevation of unsaturated fatty acids (UFAs) was positively associated with SCD1/FADS2 levels and the oncogenic capacities of OvCa cells. In contrast, pharmaceutical inhibition and genetic ablation of SCD1/FADS2 retarded tumor growth, cancer stem cell (CSC) formation and reduced platinum resistance. Inhibition of SCD1/FADS2 directly downregulated GPX4 and the GSH/GSSG ratio, causing disruption of the cellular/mitochondrial redox balance and subsequently, iron-mediated lipid peroxidation and mitochondrial dysfunction in ascites-derived OvCa cells. Combinational treatment with SCD1/FADS2 inhibitors and cisplatin synergistically repressed tumor cell dissemination, providing a promising chemotherapeutic strategy against EOC peritoneal metastases.
腹腔转移中的恶性腹水是一个富含脂质的微环境，常与上皮性卵巢癌（EOC）的不良预后有关。然而，决定卵巢癌细胞脂质代谢活性以促进肿瘤进展的详细机制仍不清楚。我们建立了大网膜条件培养基（OCM）来模拟大网膜或腹水微环境。应用质谱、RT-qPCR、免疫组化和 Western blot 检测人脂肪酸去饱和酶的表达和活性。进行药物抑制和 SCD1/FADS2 的基因敲除，以观察致癌能力。应用 RNA 测序、脂质过氧化、细胞铁、ROS 和 Mito-Stress 检测，以研究铁死亡。应用卵巢癌细胞来源的类器官和腹膜转移的小鼠模型，评估 SCD1/FADS2 抑制剂与顺铂的联合作用。我们发现，两种关键的脂肪酸去饱和酶，硬脂酰辅酶 A 去饱和酶 1（SCD1）和酰基辅酶 A6-去饱和酶（FADS2），异常上调，加速了腹水来源的 OvCa 细胞的脂质代谢活性和侵袭性。脂质组学分析显示，不饱和脂肪酸（UFAs）的升高与 SCD1/FADS2 水平和 OvCa 细胞的致癌能力呈正相关。相反，SCD1/FADS2 的药物抑制和基因敲除减缓了肿瘤生长、癌症干细胞（CSC）形成，并降低了铂耐药性。SCD1/FADS2 的抑制直接下调了 GPX4 和 GSH/GSSG 比值，导致细胞/线粒体氧化还原平衡破坏，随后铁介导的脂质过氧化和线粒体功能障碍在腹水来源的 OvCa 细胞中发生。SCD1/FADS2 抑制剂与顺铂联合治疗协同抑制肿瘤细胞扩散，为治疗 EOC 腹膜转移提供了一种有前景的化疗策略。
