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Nature. 2017 Nov 30;551(7682):639-643. doi: 10.1038/nature24637. Epub 2017 Nov 22.

NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis.

Alvarez SW1,2, Sviderskiy VO1,2, Terzi EM1,2, Papagiannakopoulos T1,2, Moreira AL1,2, Adams S1,2, Sabatini DM3,4,5,6,7, Birsoy K3,4,5,6,7,8, Possemato R1,2,3,4,5,6,7.

Author information

1
Department of Pathology, New York University School of Medicine, New York, New York 10016, USA.
2
Laura & Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, New York 10016, USA.
3
Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA.
4
Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
5
The David H. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
6
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
7
Broad Institute of Harvard and Massachusetts Institute of Technology, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA.
8
Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, 1230 York Avenue, New York 10065, USA.

Abstract

Environmental nutrient levels impact cancer cell metabolism, resulting in context-dependent gene essentiality. Here, using loss-of-function screening based on RNA interference, we show that environmental oxygen levels are a major driver of differential essentiality between in vitro model systems and in vivo tumours. Above the 3-8% oxygen concentration typical of most tissues, we find that cancer cells depend on high levels of the iron-sulfur cluster biosynthetic enzyme NFS1. Mammary or subcutaneous tumours grow despite suppression of NFS1, whereas metastatic or primary lung tumours do not. Consistent with a role in surviving the high oxygen environment of incipient lung tumours, NFS1 lies in a region of genomic amplification present in lung adenocarcinoma and is most highly expressed in well-differentiated adenocarcinomas. NFS1 activity is particularly important for maintaining the iron-sulfur co-factors present in multiple cell-essential proteins upon exposure to oxygen compared to other forms of oxidative damage. Furthermore, insufficient iron-sulfur cluster maintenance robustly activates the iron-starvation response and, in combination with inhibition of glutathione biosynthesis, triggers ferroptosis, a non-apoptotic form of cell death. Suppression of NFS1 cooperates with inhibition of cysteine transport to trigger ferroptosis in vitro and slow tumour growth. Therefore, lung adenocarcinomas select for expression of a pathway that confers resistance to high oxygen tension and protects cells from undergoing ferroptosis in response to oxidative damage.

PMID:
29168506
PMCID:
PMC5808442
DOI:
10.1038/nature24637
[Indexed for MEDLINE]
Free PMC Article

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