NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis
Open accessAbstract
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.
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Low oxygen conditions allow cells to proliferate in the absence of NFS1.
“which allows cells to proliferate in the absence of NFS1 (30, 34)”
From Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction (2022) · cites this paper as [30]
The paper reports that 3% oxygen restored proliferation in cells with NFS1 suppressed by shRNA (Abstract, page not provided). But shRNA reduced NFS1 protein by 80–95%; the experiments do not establish that cells proliferate in its complete absence. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCells require functional NFS1 to support iron-sulfur cluster synthesis to maintain viability and proliferation.
“cells require functional NFS1 to support ISC synthesis to maintain viability and proliferation (30, 34)”
From Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction (2022) · cites this paper as [30]
The paper’s Abstract identifies NFS1 as an enzyme for iron–sulfur cluster synthesis and reports that its catalytic activity is needed to rescue a proliferation defect after NFS1 suppression. But the observed proliferation requirement depends on oxygen conditions: the defect at 21% oxygen was reversed at 3% oxygen or in tumour xenografts. The unqualified claim that cells require functional NFS1 to maintain viability and proliferation is therefore broader than the reported finding. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe importance of NFS1 and ISC stability in regulation of cancer cell sensitivity to ferroptosis has been demonstrated.
“Furthermore, the importance of NFS1 and ISC stability in regulation of cancer cell sensitivity to ferroptosis has also been demonstrated (30, 31).”
From Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction (2022) · cites this paper as [30]
Iron-sulfur clusters are stabilized under low oxygen conditions (3% O2).
“ISCs are stabilized under low oxygen conditions (3% O2)”
From Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction (2022) · cites this paper as [30]
Iron-sulfur clusters are sensitive to degradation under atmospheric oxygen conditions (21% O2).
“ISCs are sensitive to degradation under atmospheric oxygen conditions (standard tissue culture is 21% O2)”
From Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction (2022) · cites this paper as [30]
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- Authors
- Alvarez, S. W., Sviderskiy, V. O., Terzi, E. M., Papagiannakopoulos, T., Moreira, A. L., Adams, S., Sabatini, D. M., Birsoy, K., & Possemato, R.
- Affiliations
- NYU Langone’s Laura and Isaac Perlmutter Cancer Center (US)
- Broad Institute (US)
- Corresponding author
- Sabatini, David M.
- Birsoy, Kıvanç
- Possemato, Richard
- ORCID
- Venue
- Nature
- Published
- 2017-11-22
- Volume
- 551
- Issue
- 7682
- Pages
- 639-643
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5808442
- OpenAlex
- W2770709665
- Cited by
- 787
- References
- 34
- Citations by year
- 2026: 63 · 2025: 90 · 2024: 116 · 2023: 105 · 2022: 138 · 2021: 148 · 2020: 57 · 2019: 46 · 2018: 20 · 2017: 2
- FWCI
- 28.28
- Type
- journal article
- Language
- en
- Update notices
- correction (2022-09-14)
- Open access
- bronze
- doi.org
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- PMC
- Funders
- Leukemia and Lymphoma Society
- Broad Institute
- Agios Pharmaceuticals
- Scheme for Promotion of Academic and Research Collaboration
- National Institutes of Health (1s10od018338-01, 1s10od010584-01a1, 1s10od016304-01, CA129105, CA168940)
- National Cancer Institute (K99CA168940, R01CA103866, K22CA193660, R01CA129105, R00CA168940, P30CA016087)
- National Institute of General Medical Sciences (T32GM007308, T32GM115313)
- National Institute of Allergy and Infectious Diseases (T32AI007389, R37AI047389)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Keywords
- NFS1, iron-sulfur cluster assembly, ferroptosis, lung adenocarcinoma, tumor hypoxia, high oxygen tension, oxidative damage, iron starvation response, glutathione synthesis, cysteine transport, gene amplification, tumour metastasis, cancer metabolism
- MeSH terms
- Animals, Carcinoma, Non-Small-Cell Lung, Cysteine, Glutathione, Humans, Iron-Sulfur Proteins, Lung Neoplasms, Neoplasm Metastasis, Oxygen, Carbon-Sulfur Lyases, Cell Death, Oxidative Stress, RNA Interference, Cell Line, Tumor, Mice
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