2. Academic Validation
  3. ACSL4 and polyunsaturated lipids support metastatic extravasation and colonization

ACSL4 and polyunsaturated lipids support metastatic extravasation and colonization

  • Cell. 2024 Nov 19:S0092-8674(24)01270-4. doi: 10.1016/j.cell.2024.10.047.
Yuqi Wang 1,  Mangze Hu 2,  Jian Cao 3,  Fengxiang Wang 4,  Jingrong Regina Han 5,  Tianshu William Wu 4,  Luxiao Li 1,  Jinshi Yu 6,  Yujing Fan 6,  Guanglei Xie 7,  Heyuan Lian 6,  Yueying Cao 3,  Nathchar Naowarojna 6,  Xi Wang 8,  Yilong Zou 9
Affiliations

Affiliations

  • 1 Westlake Four-Dimensional Dynamic Metabolomics (Meta4D) Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China; School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China; Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China; Research Center for Industries of the Future, Westlake University, Hangzhou, Zhejiang, China.
  • 2 Westlake Four-Dimensional Dynamic Metabolomics (Meta4D) Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China; School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China.
  • 3 Department of Gynecology, Women's Hospital of Nanjing Medical University, Nanjing Women and Children's Healthcare Hospital, Nanjing, Jiangsu, China.
  • 4 Westlake Four-Dimensional Dynamic Metabolomics (Meta4D) Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China; School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China; Research Center for Industries of the Future, Westlake University, Hangzhou, Zhejiang, China; College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
  • 5 Westlake Four-Dimensional Dynamic Metabolomics (Meta4D) Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China; School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China; Research Center for Industries of the Future, Westlake University, Hangzhou, Zhejiang, China; School of Life Sciences, Fudan University, Shanghai, China.
  • 6 Westlake Four-Dimensional Dynamic Metabolomics (Meta4D) Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China.
  • 7 School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China; Westlake Bioinformatics and Genomics Lab, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China.
  • 8 School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China; Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China; Westlake Bioinformatics and Genomics Lab, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China. Electronic address: wangxi@westlake.edu.cn.
  • 9 Westlake Four-Dimensional Dynamic Metabolomics (Meta4D) Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China; School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China; Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China; Research Center for Industries of the Future, Westlake University, Hangzhou, Zhejiang, China. Electronic address: zouyilong@westlake.edu.cn.
PMID: 39591965 DOI: 10.1016/j.cell.2024.10.047
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.

Keywords

ACSL4; ECH1; cancer metastasis; extravasation; ferroptosis susceptibility; in vivo CRISPR screens; lipid metabolism; metastatic colonization; ovarian cancer; polyunsaturated lipids.

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