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Nature. 2019 Mar;567(7746):118-122. doi: 10.1038/s41586-019-0945-5. Epub 2019 Feb 13.

Squalene accumulation in cholesterol auxotrophic lymphomas prevents oxidative cell death.

Author information

1
Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, NY, USA.
2
Department of Chemistry, Columbia University, New York, NY, USA.
3
Kavli Institute for Brain Science, Columbia University, New York, NY, USA.
4
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
5
Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.
6
Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
7
Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
8
The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, USA.
9
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
10
Broad Institute of Harvard and MIT, Cambridge, MA, USA.
11
Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, NY, USA. kbirsoy@rockefeller.edu.

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.

PMID:
30760928
PMCID:
PMC6405297
DOI:
10.1038/s41586-019-0945-5
[Indexed for MEDLINE]
Free PMC Article

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