NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis
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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
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Nature Publishing Group
2018
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| Online Access: | http://hdl.handle.net/1721.1/116767 https://orcid.org/0000-0002-1446-7256 https://orcid.org/0000-0002-2401-0030 |
| _version_ | 1811084761487114240 |
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| author | Alvarez, Samantha W. Sviderskiy, Vladislav O. Terzi, Erdem M. Papagiannakopoulos, Thales Moreira, Andre L. Adams, Sylvia Birsoy, Kıvanç Sabatini, David Possemato, Richard |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Alvarez, Samantha W. Sviderskiy, Vladislav O. Terzi, Erdem M. Papagiannakopoulos, Thales Moreira, Andre L. Adams, Sylvia Birsoy, Kıvanç Sabatini, David Possemato, Richard |
| author_sort | Alvarez, Samantha W. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T12:57:10Z |
| format | Article |
| id | mit-1721.1/116767 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T12:57:10Z |
| publishDate | 2018 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/1167672022-09-28T11:07:21Z NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis Alvarez, Samantha W. Sviderskiy, Vladislav O. Terzi, Erdem M. Papagiannakopoulos, Thales Moreira, Andre L. Adams, Sylvia Birsoy, Kıvanç Sabatini, David Possemato, Richard Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Sabatini, David Possemato, Richard 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. 2018-07-03T18:14:37Z 2018-07-03T18:14:37Z 2017-11 2016-05 2018-07-03T17:48:59Z Article http://purl.org/eprint/type/JournalArticle 0028-0836 1476-4687 http://hdl.handle.net/1721.1/116767 Alvarez, Samantha W. et al. “NFS1 Undergoes Positive Selection in Lung Tumours and Protects Cells from Ferroptosis.” Nature (November 2017) © 2017 Macmillan Publishers Limited, part of Springer Nature https://orcid.org/0000-0002-1446-7256 https://orcid.org/0000-0002-2401-0030 http://dx.doi.org/10.1038/NATURE24637 Nature Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Nature Publishing Group PMC |
| spellingShingle | Alvarez, Samantha W. Sviderskiy, Vladislav O. Terzi, Erdem M. Papagiannakopoulos, Thales Moreira, Andre L. Adams, Sylvia Birsoy, Kıvanç Sabatini, David Possemato, Richard NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis |
| title | NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis |
| title_full | NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis |
| title_fullStr | NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis |
| title_full_unstemmed | NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis |
| title_short | NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis |
| title_sort | nfs1 undergoes positive selection in lung tumours and protects cells from ferroptosis |
| url | http://hdl.handle.net/1721.1/116767 https://orcid.org/0000-0002-1446-7256 https://orcid.org/0000-0002-2401-0030 |
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