Letter

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

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Accepted:
Published online:

Abstract

Environmental nutrient levels impact cancer cell metabolism, resulting in context-dependent gene essentiality1,2. 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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Acknowledgements

We thank members of the laboratories of D.M.S., K.B. and R.P.; G. Georgiou and E. Stone for cyst(e)inase; C. Moraes, and I. F. M. de Coo for wild-type 143B and CYTB 143B cells; P. Thiru for bioinformatic support; C. Loomis, L. Chiriboga, and B. Zeck for histology. Research was supported by a gift from Agios Pharmaceuticals to D.M.S., National Institutes of Health (NIH) (T32GM007308 and T32GM115313 supporting V.O.S.; CA168940 to R.P., CA193660 to K.B., and CA103866, CA129105, and AI07389 to D.M.S.), Starr Cancer Consortium and Broad Institute SPARC to D.M.S., Leukemia and Lymphoma Society Special Fellow Award to K.B., V Foundation to R.P., Pew-Stewart Scholar Grant to R.P., Susan G. Komen for the Cure to R.P. D.M.S. is an investigator of the Howard Hughes Medical Institute. Experimental Pathology Resource Center supported by the NIH (P30CA016087, S10 OD010584-01, and S10 OD018338). Immune Monitoring Core supported by the NIH (S10 OD016304).

Author information

Author notes

    • Samantha W. Alvarez
    •  & Vladislav O. Sviderskiy

    These authors contributed equally to this work.

    • Kıvanç Birsoy
    •  & Richard Possemato

    Present addresses: Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA (K.B.); Department of Pathology, New York University School of Medicine, New York, New York 10016, USA (R.P.).

Affiliations

  1. Department of Pathology, New York University School of Medicine, New York, New York 10016, USA.

    • Samantha W. Alvarez
    • , Vladislav O. Sviderskiy
    • , Erdem M. Terzi
    • , Thales Papagiannakopoulos
    • , Andre L. Moreira
    • , Sylvia Adams
    •  & Richard Possemato
  2. Laura & Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, New York 10016, USA

    • Samantha W. Alvarez
    • , Vladislav O. Sviderskiy
    • , Erdem M. Terzi
    • , Thales Papagiannakopoulos
    • , Andre L. Moreira
    • , Sylvia Adams
    •  & Richard Possemato
  3. Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA

    • David M. Sabatini
    • , Kıvanç Birsoy
    •  & Richard Possemato
  4. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    • David M. Sabatini
    • , Kıvanç Birsoy
    •  & Richard Possemato
  5. The David H. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA

    • David M. Sabatini
    • , Kıvanç Birsoy
    •  & Richard Possemato
  6. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    • David M. Sabatini
    • , Kıvanç Birsoy
    •  & Richard Possemato
  7. Broad Institute of Harvard and Massachusetts Institute of Technology, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA

    • David M. Sabatini
    • , Kıvanç Birsoy
    •  & Richard Possemato
  8. Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, 1230 York Avenue, New York 10065, USA

    • Kıvanç Birsoy

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Contributions

R.P., K.B., and D.M.S conceived the project and designed the experiments. R.P. and K.B. performed RNAi screens. T.P. assisted with the KP model and performed intratracheal instillations. A.L.M. and S.A. evaluated histopathology. S.W.A., V.O.S., E.M.T., and R.P. performed follow-up validation experiments. R.P., K.B., and D.M.S wrote and edited the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to David M. Sabatini or Kıvanç Birsoy or Richard Possemato.

Reviewer Information Nature thanks P. Storz and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains the supplementary discussion, supplementary references, raw images of the immunoblots and the flow cytometry gating strategy.

  2. 2.

    Life Sciences Reporting Summary

Excel files

  1. 1.

    Supplementary Table 1

    This table contains simultaneous in vivo and in vitro screening data.

  2. 2.

    Supplementary Table 2

    This table contains a curated list of 25 common metabolites utilized by the enzymes screened.

  3. 3.

    Supplementary Table 3

    This table contains primary screening data, 21% oxygen and 3% oxygen.

  4. 4.

    Supplementary Table 4

    This table shows overlap of shRNAs scoring in both screens.

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