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Squalene accumulation in cholesterol auxotrophic lymphomas prevents oxidative cell death

Author

Listed:
  • Javier Garcia-Bermudez

    (The Rockefeller University)

  • Lou Baudrier

    (The Rockefeller University)

  • Erol Can Bayraktar

    (The Rockefeller University)

  • Yihui Shen

    (Columbia University
    Columbia University)

  • Konnor La

    (The Rockefeller University)

  • Rohiverth Guarecuco

    (The Rockefeller University)

  • Burcu Yucel

    (The Rockefeller University)

  • Danilo Fiore

    (Weill Cornell Medical College
    University of Turin)

  • Bernardo Tavora

    (The Rockefeller University)

  • Elizaveta Freinkman

    (Whitehead Institute for Biomedical Research)

  • Sze Ham Chan

    (Whitehead Institute for Biomedical Research)

  • Caroline Lewis

    (Whitehead Institute for Biomedical Research)

  • Wei Min

    (Columbia University
    Columbia University)

  • Giorgio Inghirami

    (Weill Cornell Medical College
    University of Turin)

  • David M. Sabatini

    (Whitehead Institute for Biomedical Research
    Massachusetts Institute of Technology
    The David H. Koch Institute for Integrative Cancer Research at MIT
    Massachusetts Institute of Technology)

  • Kıvanç Birsoy

    (The Rockefeller University)

Abstract

Cholesterol is essential for cells to grow and proliferate. Normal mammalian cells meet their need for cholesterol through its uptake or de novo synthesis1, but the extent to which cancer cells rely on each of these pathways remains poorly understood. Here, using a competitive proliferation assay on a pooled collection of DNA-barcoded cell lines, we identify a subset of cancer cells that is auxotrophic for cholesterol and thus highly dependent on its uptake. Through metabolic gene expression analysis, we pinpoint the loss of squalene monooxygenase expression as a cause of cholesterol auxotrophy, particularly in ALK+ anaplastic large cell lymphoma (ALCL) cell lines and primary tumours. Squalene monooxygenase catalyses the oxidation of squalene to 2,3-oxidosqualene in the cholesterol synthesis pathway and its loss results in accumulation of the upstream metabolite squalene, which is normally undetectable. In ALK+ ALCLs, squalene alters the cellular lipid profile and protects cancer cells from ferroptotic cell death, providing a growth advantage under conditions of oxidative stress and in tumour xenografts. Finally, a CRISPR-based genetic screen identified cholesterol uptake by the low-density lipoprotein receptor as essential for the growth of ALCL cells in culture and as patient-derived xenografts. This work reveals that the cholesterol auxotrophy of ALCLs is a targetable liability and, more broadly, that systematic approaches can be used to identify nutrient dependencies unique to individual cancer types.

Suggested Citation

  • Javier Garcia-Bermudez & Lou Baudrier & Erol Can Bayraktar & Yihui Shen & Konnor La & Rohiverth Guarecuco & Burcu Yucel & Danilo Fiore & Bernardo Tavora & Elizaveta Freinkman & Sze Ham Chan & Caroline, 2019. "Squalene accumulation in cholesterol auxotrophic lymphomas prevents oxidative cell death," Nature, Nature, vol. 567(7746), pages 118-122, March.
  • Handle: RePEc:nat:nature:v:567:y:2019:i:7746:d:10.1038_s41586-019-0945-5
    DOI: 10.1038/s41586-019-0945-5
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    Cited by:

    1. Anna S. Dickson & Tekle Pauzaite & Esther Arnaiz & Brian M. Ortmann & James A. West & Norbert Volkmar & Anthony W. Martinelli & Zhaoqi Li & Niek Wit & Dennis Vitkup & Arthur Kaser & Paul J. Lehner & J, 2023. "A HIF independent oxygen-sensitive pathway for controlling cholesterol synthesis," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Guoshu Bi & Jiaqi Liang & Yunyi Bian & Guangyao Shan & Yiwei Huang & Tao Lu & Huan Zhang & Xing Jin & Zhencong Chen & Mengnan Zhao & Hong Fan & Qun Wang & Boyi Gan & Cheng Zhan, 2024. "Polyamine-mediated ferroptosis amplification acts as a targetable vulnerability in cancer," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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