biostudies-literatureAlvarez SWNIAID NIH HHSNCI NIH HHSNIH HHSNIGMS NIH HHS639-643https://www.ebi.ac.uk/biostudies/studies/S-EPMC5808442biostudies-literatureUnknown551(7682)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 weNatureNFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis.PMC5808442K22 CA193660S10 OD010584-01K99 CA168940R01 CA129105T32 GM115313T32 AI007389R01 CA103866R37 AI047389S10 OD010584T32 GM007308S10 OD016304S10 OD018338CA168940P30 CA016087R00 CA168940Papagiannakopoulos TSabatini DMBirsoy KPossemato RSviderskiy VOAdams SMoreira ALAlvarez SWTerzi EMfalseNFS1 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 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 we2017-01-01T00:00:00Z2017 Nov2025-04-04T14:48:44.788Z2019-03-26T23:38:23ZS-EPMC58084422916850610.1038/nature24637