Squalene accumulation in cholesterol auxotrophic lymphomas prevents oxidative cell death
Authors: Caroline Lewis
Elizaveta Freinkman
Javier Garcia-Bermudez
Burcu Yucel
Giorgio Inghirami
Danilo Fiore
Rohiverth Guarecuco
Kıvanç Birsoy
Erol Can Bayraktar
Sze Ham Chan
Konnor La
Yihui Shen
Wei Min
Bernardo Tavora
David M Sabatini
Lou Baudrier
Journal: Nature (2019)
Discipline: Multidisciplinary
Keywords: Cholesterol; Cancer cells; Uptake; De novo synthesis; Squalene monooxygenase
Affiliations: Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, NY, USA., Department of Chemistry, Columbia University, New York, NY, USA., Kavli Institute for Brain Science, Columbia University, New York, NY, USA., Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA., Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy., Whitehead Institute for Biomedical Research, Cambridge, MA, USA., Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA., The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, USA., Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA., Broad Institute of Harvard and MIT, Cambridge, MA, USA., Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, NY, USA. .

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. 

Retracted: No

PubPeer comments:
 Figure 3A and 3G appear to have a few figures which may overlap. *** ![file] , 
 Figure 2B appears to have a repeated image. *** ![file] , 
 Figures 5A and 6E appear to have a repeated set of images (blue boxes) and one set of images with a small area of overlap (red boxes). *** ![file] , 
 Two images in Figure 3C may also have an area of overlap, although the resolution makes it difficult to be certain. *** ![file] , 
 #3 Perhaps awkwardly, this image and this paper appears to have been featured on the cover of this journal. *** ![file] , 
 October 8, 2021  This article (IL-6 Promotes Cancer Stemness and Oncogenicity in U2OS and MG-63 Osteosarcoma Cells by Upregulating the OPN-STAT3 Pathway. Chuan Zhang, Kun Ma, Wu-Yin Li. J Cancer 2019; 10(26):6511-6525) has been retracted due to concerns on multiple image duplications as identified by PubPeer users. The corresponding author has been contacted by the journal, and the authors expressed apology for their negligence and mistakes in this paper. , 
 There appears to be some images in this paper which appear in at least one other paper (in some cases after rotation), seemingly with a set of 4 papers involved. There seems to be two papers with common authors, but the others seem unrelated. Of note, the Journal of Cancer (2019) was retracted u201cdue to concerns on multiple image duplications as identified by PubPeer users. The corresponding author has been contacted by the journal, and the authors expressed apology for their negligence and mistakes in this paper.u201d Figure 2D (upper left) Journal of Cancer (2022) doi: 10.7150 jca.62787 Received 15 May 2021 https: pubpeer.com publications B4EEF4C364C4CFD562DDCB029F965F Figure 3C (lower left) OncoTargets and Therapy (2020) doi:10.2147 ott.s217745 Received 30 May 2019 https: pubpeer.com publications 6A7FD31BAF2A764D5A0FC4CD928807 Figure 2J (upper right) Cell Proliferation (2020) doi: 10.1111 cpr.12833 Received: 14 January 2020 https: pubpeer.com publications E895DBD3B6277460E277A43926A185 Figure 2B (lower right) Journal of Cancer (2019) RETRACTED doi: 10.7150 jca.29931 Received 12 December 2018 https: pubpeer.com publications F8CD809499CDCEC1BB53327CE808A0 *** ![file] *** Acknowledgements This study was supported by grants from the Natural Science Foundation of Henan Province, China (No. 182102310389) and the Scientific Research of traditional Chinese Medicine of Henan Province (No. 2017ZY2122 and No. 2018ZY1022). ,