Squalene accumulation in cholesterol auxotrophic lymphomas prevents oxidative cell death.

TitleSqualene accumulation in cholesterol auxotrophic lymphomas prevents oxidative cell death.
Publication TypeJournal Article
Year of Publication2019
AuthorsGarcia-Bermudez J, Baudrier L, Bayraktar ECan, Shen Y, La K, Guarecuco R, Yucel B, Fiore D, Tavora B, Freinkman E, Chan SHam, Lewis C, Min W, Inghirami G, Sabatini DM, Birsoy K
JournalNature
Volume567
Issue7746
Pagination118-122
Date Published2019 03
ISSN1476-4687
KeywordsAged, Animals, Apoptosis, Cell Line, Tumor, Cell Proliferation, Cholesterol, DNA Barcoding, Taxonomic, Farnesyl-Diphosphate Farnesyltransferase, Female, Humans, Iron, Lymphoma, Large-Cell, Anaplastic, Male, Membrane Lipids, Mice, Mice, Inbred NOD, Oxidative Stress, Receptors, LDL, Squalene, Squalene Monooxygenase, Young Adult
Abstract

Cholesterol is essential for cells to grow and proliferate. Normal mammalian cells meet their need for cholesterol through its uptake or de novo synthesis, 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.

DOI10.1038/s41586-019-0945-5
Alternate JournalNature
PubMed ID30760928
PubMed Central IDPMC6405297
Grant ListR01 CA103866 / CA / NCI NIH HHS / United States
K22 CA193660 / CA / NCI NIH HHS / United States
R37 AI047389 / AI / NIAID NIH HHS / United States
R01 EB020892 / EB / NIBIB NIH HHS / United States
DP2 CA228042 / CA / NCI NIH HHS / United States