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
  • 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: [email protected].
  • 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: [email protected].
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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