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NFS1 Undergoes Positive Selection in Lung Tumors and Protects Cells From Elevated Oxygen Levels and Ferroptosis

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Alvarez SW*, Sviderskiy VO*, Terzi EM, Papagiannakopoulos T, Moreira AL, Adams S, Sabatini DM, Birsoy K, and Possemato R. Nature. 2017 Nov 30.

Environmental nutrient levels impact cancer cell metabolism, resulting in context-dependent gene essentiality. Here, using RNAi-based loss of function screening, we identify environmental oxygen level as 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 (ISC) biosynthetic enzyme NFS1. Accordingly, mammary or subcutaneous tumours grow despite NFS1 suppression, while 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 ISC cofactors present in multiple cell-essential proteins upon exposure to O2 compared to other forms of oxidative damage. Additionally, insufficient ISC maintenance robustly activates the iron-starvation response and, in combination with glutathione biosynthesis inhibition, 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.

Selected Publications

View ArticleMinton DR NM, McLaughlin DJ, Shin J, Bayraktar EC, Alvarez SW, Sviderskiy VO, Papagiannakopoulos T, Sabatini DM, Birsoy K, Possemato R. Serine Catabolism by SHMT2 is Required for Proper Mitochondrial Translation Initiation and Maintenance of Formylmethionyl tRNAs. Molecular cell.

View Article Download PDFAlvarez SW and Possemato R. Leveraging the iron-starvation response to promote ferroptosis, Oncotarget, 2018, Vol. 9, (No. 13), pp: 10830-10831.

View ArticleVaeth M, Maus M, Klein-Hessling S, Freinkman E, Yang J, Eckstein M, Cameron S, Turvey SE, Sefling E, Berberich-Siebelt F, Possemato R, Feske S. Store-operated Ca2+ entry, calcineurin and NFAT control clonal expansion of T cells through metabolic reprogramming, Immunity, 2017 Oct 17;47(4):664-679.e6.

View Article Download PDFSayin V, LeBoeuf S, Singh S, Davidson S, Biancur D, Guzelhan B, Alvarez SW, Wu WL, Karakousi TR, Zavitsanou AM, Ubriaco J, Muir A, Karagiannis D, Morris PJ, Thomas CJ, Possemato R, Vander Heiden MG, Papagiannakopoulos T. Activation of the NRF2 antioxidant program causes defects in central carbon metabolism, eLife, 2017;6:e28083.

View Article Download PDFPacold ME, Brimacombe KR, Chan SH, Rohde JM, Lewis CA, Swier LJ, Possemato R, Chen WW, Sullivan LB, Fiske BP, Cho S, Freinkman E, Birsoy K, Abu-Remaileh M, Shaul YD, Liu CM, Zhou M, Koh MJ, Chung H, Davidson SM, Luengo A, Wang AQ, Xu X, Yasgar A, Liu L, Rai G, Westover KD, Vander Heiden MG, Shen M, Gray NS, Boxer MB, Sabatini DM. A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate. Nat Chem Biol. 2016 Jun;12(6):452-8.

View Article Download PDFTsun ZY, Possemato R. Amino Acid Management in Cancer. Semin Cell Dev Biol. 2015 Aug 12 pii: S1084-9521(15)00146-9.

View Article Download PDFStrohecker A, Joshi S, Possemato R, Abraham R, Sabatini DM, White E. Identification of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB4) as a Novel Autophagy Regulator by High Content shRNA Screening. Oncogene. 2015 Mar 16.

View Article Download PDFKim D, Fiske BP, Birsoy K, Kami K, Possemato R, Chudnovsky Y, Pacold ME, Freinkman E, Chen WW, Shelton LM, Gui DY, Kwon M, Kang SW, Snuderl M, Vander Heiden MG, Sabatini DM. SHMT2 drives glioma
cell survival in the tumor microenvironment but imposes a liability for glycine toxicity. Nature. 2015 Apr 8.

View Article Download PDFShaul YD, Freinkman E, Comb WC, Cantor JR, Tam WL, Thiru P, Kim D, Kanarek N, Pacold ME, Chen WW, Bierie B, Possemato R, Reinhardt F, Weinberg RA, Yaffe MB, Sabatini DM. Dihydropyrimidine accumulation is required for the epithelial-mesenchymal transition. Cell. 2014;158(5):1094-109.

View Article Download PDFBirsoy K*, Possemato R*, Lorbeer FK, Bayraktar EC, Thiru P, Yucel B, Wang T, Chen WW, Clish CB, Sabatini DM. Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides. Nature. 2014;508(7494):108-12.

View Article Download PDFGrabiner BC, Nardi V, Birsoy K, Possemato R, Shen K, Sinha S, Jordan A, Beck AH, Sabatini DM. A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity. Cancer discovery. 2014;4(5):554-63.

View Article Download PDFBirsoy K, Wang T, Possemato R, Yilmaz OH, Koch CE, Chen WW, Hutchins AW, Gultekin Y, Peterson TR, Carette JE, Brummelkamp TR, Clish CB, Sabatini DM. MCT1-mediated transport of a toxic molecule is an effective strategy for targeting glycolytic tumors. Nature genetics. 2013;45(1):104-8.

View Article Download PDFNguyen CL*, Possemato R*, Bauerlein EL, Xie A, Scully R, Hahn WC. Nek4 regulates entry into replicative senescence and the response to DNA damage in human fibroblasts. Molecular and cellular biology. 2012;32(19):3963-77.

View Article Download PDFBirsoy K, Sabatini DM, Possemato R. Untuning the tumor metabolic machine: Targeting cancer metabolism: a bedside lesson. Nature medicine. 2012;18(7):1022-3.

View Article Download PDFPossemato R, Marks KM, Shaul YD, Pacold ME, Kim D, Birsoy K, Sethumadhavan S, Woo HK, Jang HG, Jha AK, Chen WW, Barrett FG, Stransky N, Tsun ZY, Cowley GS, Barretina J, Kalaany NY, Hsu PP, Ottina K, Chan AM, Yuan B, Garraway LA, Root DE, Mino-Kenudson M, Brachtel EF, Driggers EM, Sabatini DM. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature. 2011;476(7360):346-50.

View Article Download PDFMaida Y, Yasukawa M, Furuuchi M, Lassmann T, Possemato R, Okamoto N, Kasim V, Hayashizaki Y, Hahn WC, Masutomi K. An RNA-dependent RNA polymerase formed by TERT and the RMRP RNA. Nature. 2009;461(7261):230-5.

View Article Download PDFPossemato R, Timmons JC, Bauerlein EL, Wada N, Baldwin A, Masutomi K, Hahn WC. Suppression of hPOT1 in diploid human cells results in an hTERT-dependent alteration of telomere length dynamics. Molecular cancer research : MCR. 2008;6(10):1582-93.

View Article Download PDFMasutomi K, Possemato R, Wong JM, Currier JL, Tothova Z, Manola JB, Ganesan S, Lansdorp PM, Collins K, Hahn WC. The telomerase reverse transcriptase regulates chromatin state and DNA damage responses. Proceedings of the National Academy of Sciences of the United States of America. 2005;102(23):8222-7.

View Article Download PDFChen W*, Possemato R*, Campbell KT, Plattner CA, Pallas DC, Hahn WC. Identification of specific PP2A complexes involved in human cell transformation. Cancer cell. 2004;5(2):127-36.

> View Article Download PDFPossemato R, Eggan K, Moeller BJ, Jaenisch R, Jackson-Grusby L. Flp recombinase regulated lacZ expression at the ROSA26 locus. Genesis. 2002;32(2):184-6.

View Article Download PDFJackson-Grusby L, Beard C, Possemato R, Tudor M, Fambrough D, Csankovszki G, Dausman J, Lee P, Wilson C, Lander E, Jaenisch R. Loss of genomic methylation causes p53-dependent apoptosis and epigenetic deregulation. Nature genetics. 2001;27(1):31-9.