近日，西湖大学邹贻龙等研究人员合作发现，ACSL4和多不饱和脂质支持转移性外渗和定植。2024年11月25日，《细胞》杂志在线发表了这项成果。

研究人员揭示了转移潜力与铁死亡易感性之间的关联。在卵巢癌患者的转移性癌细胞中，铁死亡敏感性和多不饱和脂肪酰（PUFA）脂质含量较来自原发肿瘤的细胞更高。

通过两轮体内选择建立的，卵巢癌远程转移小鼠模型中的代谢聚焦CRISPR筛选发现，多不饱和脂肪酸脂质合成酶——长链酰基辅酶A合成酶家族成员4（ACSL4）是促血源性转移的因素。ACSL4通过增强膜流动性和细胞侵袭性促进转移性外渗。

在促进转移的同时，高PUFA脂质状态依赖于含有水解酶结构域6酰甘油脂肪酶（ABHD6）、烯酰辅酶A δ异构酶1（ECI1）和烯酰辅酶A水合酶1（ECH1）——这些限速酶为不饱和脂肪酸（UFA）的β-氧化做准备。ACSL4/ECH1的共同抑制显著抑制了转移。

该研究揭示了PUFA脂质在肿瘤进展和转移中的双重功能，这一机制可能为治疗开发提供可利用的靶点。

据悉，癌细胞向远处器官的转移扩散，要求癌细胞具有高度的形态和代谢适应性。然而，细胞脂质组对转移的贡献仍然是未知的。

附：英文原文

Title: ACSL4 and polyunsaturated lipids support metastatic extravasation and colonization

Author: Yuqi Wang, Mangze Hu, Jian Cao, Fengxiang Wang, Jingrong Regina Han, Tianshu William Wu, Luxiao Li, Jinshi Yu, Yujing Fan, Guanglei Xie, Heyuan Lian, Yueying Cao, Nathchar Naowarojna, Xi Wang, Yilong Zou

Issue&Volume: 2024-11-25

Abstract: Metastatic dissemination to distant organs demands that cancer cells possess high morphological and metabolic adaptability. However, contributions of the cellular lipidome to metastasis remain elusive. Here, we uncover a correlation between metastasis potential and ferroptosis susceptibility in multiple cancers. Metastases-derived cancer cells exhibited higher ferroptosis sensitivity and polyunsaturated fatty acyl (PUFA)-lipid contents than primary-tumor-derived cells from ovarian cancer patients. Metabolism-focused CRISPR screens in a mouse model for ovarian cancer distant metastasis established via two rounds of in vivo selection revealed the PUFA-lipid biosynthesis enzyme acyl-coenzyme A (CoA) synthetase long-chain family member 4 (ACSL4) as a pro-hematogenous metastasis factor. ACSL4 promotes metastatic extravasation by enhancing membrane fluidity and cellular invasiveness. While promoting metastasis, the high PUFA-lipid state creates dependencies on abhydrolase-domain-containing 6, acylglycerol lipase (ABHD6), enoyl-CoA delta isomerase 1 (ECI1), and enoyl-CoA hydratase 1 (ECH1)—rate-limiting enzymes preparing unsaturated fatty acids (UFAs) for β-oxidation. ACSL4/ECH1 co-inhibition achieved potent suppression of metastasis. Our work establishes the dual functions of PUFA-lipids in tumor progression and metastasis that may be exploitable for therapeutic development.

DOI: 10.1016/j.cell.2024.10.047

Source: https://www.cell.com/cell/abstract/S0092-8674(24)01270-4