Journal Article

Squalene accumulation in cholesterol auxotrophic lymphomas prevents oxidative cell death

Chan, Sze Ham, Tavora, Bernardo, Min, Wei, Inghirami, Giorgio, Bayraktar, Erol Can, Sabatini, David M., Guarecuco, Rohiverth, La, Konnor, Fiore, Danilo, Baudrier, Lou, Shen, Yihui, Freinkman, Elizaveta, Birsoy, Kıvanç, Garcia-Bermudez, Javier, Yucel, Burcu, Lewis, Caroline

2019

Overview

Cholesterol is essential for cells to grow and proliferate. Normal mammalian cells meet their need for cholesterol through its uptake or de novo synthesis 1 , 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. The authors find that loss of squalene monooxygenase expression alters the lipid metabolism of cancer cells, which confers protection from ferroptotic cell death and thus promotes tumour growth.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 38/47 / 45/22 / 45/44 / 631/45/320 / 631/67/2327 / 64 / 64/60 / Accumulation / Aged / Aluminum compounds / Anaplastic large-cell lymphoma / Animals / Apoptosis / Automation / Auxotrophy / Bar codes / Biochemistry / Biosynthesis / Biotechnology / Cancer / Cancer cells / Cancer prevention / Cancer research / Cell culture / Cell death / Cell Line, Tumor / Cell Proliferation / Cells (Biology) / Cholesterol / Cholesterol - biosynthesis / Cholesterol - metabolism / CRISPR / Deoxyribonucleic acid / DNA / DNA Barcoding, Taxonomic / DNA methylation / Encyclopedias / Farnesyl-Diphosphate Farnesyltransferase - genetics / Farnesyl-Diphosphate Farnesyltransferase - metabolism / Female / Gene expression / Genes / Genetic screening / Genetic testing / Health screening / Humanities and Social Sciences / Humans / Iron - metabolism / Kinases / Legal liability / Letter / Liability / Lipids / Lipoproteins / Low density lipoproteins / Lymphoma / Lymphoma, Large-Cell, Anaplastic - enzymology / Lymphoma, Large-Cell, Anaplastic - metabolism / Lymphoma, Large-Cell, Anaplastic - pathology / Lymphomas / Male / Membrane Lipids - chemistry / Membrane Lipids - metabolism / Metabolism / Metabolites / Mice / Mice, Inbred NOD / Microscopy / multidisciplinary / Mutation / Oxidation / Oxidation-reduction reactions / Oxidative Stress / Receptor density / Receptors, LDL - genetics / Receptors, LDL - metabolism / Science / Science (multidisciplinary) / Squalene / Squalene - metabolism / Squalene monooxygenase / Squalene Monooxygenase - genetics / Squalene Monooxygenase - metabolism / Sterols / Synthesis / Tumor cell lines / Tumors / Xenografts / Xenotransplantation / Young Adult