Squalene accumulation in cholesterol auxotrophic lymphomas prevents oxidative cell death
Name
nihms-1518743.pdf
Description
Accepted version
Size
2.88 MB
Format
Adobe PDF
Checksum (MD5)
a70d38fd6ebca1e83b8329172ef1bd69
Author(s)
Freinkman, Elizaveta
Chan, Sze Ham
Lewis, Caroline
Sabatini, David M.
Date Issued
February 13, 2019
Journal
Nature
Publisher
Springer Science and Business Media LLC
Citation
Garcia-Bermudez, Javier et al. “Squalene accumulation in cholesterol auxotrophic lymphomas prevents oxidative cell death.” Nature 567 (2019): 118-122 © 2019 The Author(s)
Version
Author's final manuscript
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.
Subjects
Multidisciplinary
MIT Department
Whitehead Institute for Biomedical Research
Terms of Use
Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1038/s41586-019-0945-5
