Publications

Featured Publication:

Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides

View Article Download PDFBirsoy K*, Possemato R*, Lorbeer FK, Bayraktar EC, Thiru P, Yucel B, Wang T, Chen WW, Clish CB, Sabatini DM. Nature. 2014;508(7494):108-12.

As the concentrations of highly consumed nutrients, particularly glucose, are generally lower in tumours than in normal tissues, cancer cells must adapt their metabolism to the tumour microenvironment. A better understanding of these adaptations might reveal cancer cell liabilities that can be exploited for therapeutic benefit. Here we developed a continuous-flow culture apparatus (Nutrostat) for maintaining proliferating cells in low-nutrient media for long periods of time, and used it to undertake competitive proliferation assays on a pooled collection of barcoded cancer cell lines cultured in low-glucose conditions. Sensitivity to low glucose varies amongst cell lines, and an RNA interference (RNAi) screen pinpointed mitochondrial oxidative phosphorylation (OXPHOS) as the major pathway required for optimal proliferation in low glucose. We found that cell lines most sensitive to low glucose are defective in the OXPHOS upregulation that is normally caused by glucose limitation as a result of either mitochondrial DNA (mtDNA) mutations in complex I genes or impaired glucose utilization. These defects predict sensitivity to biguanides, antidiabetic drugs that inhibit OXPHOS, when cancer cells are grown in low glucose or as tumour xenografts. Notably, the biguanide sensitivity of cancer cells with mtDNA mutations was reversed by ectopic expression of yeast NDI1, a ubiquinone oxidoreductase that allows bypass of complex I function. Thus, we conclude that mtDNA mutations and impaired glucose utilization are potential biomarkers for identifying tumours with increased sensitivity to OXPHOS inhibitors.

Selected Publications

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.