Professor Graeber’s group is working to understand cancer signaling from a systems viewpoint. They focus on developing genome- and proteome-wide detection assays, applying these assays to measuring and computationally modeling abberant cancer signaling, and translating their discoveries to clinical applications. They have developed a quantitative mass spectrometry-based protocol for identifying tyrosine-phosphorylated proteins from cancer cell lysates. They are using this proteome-wide “phosphorlation profiling” assay to identify the signaling pathways activated by various oncogenic initiating events (e.g. kinase mutations), and to elucidate the interconnectedness of classical signaling pathways into a more comprehensive signaling network. In modeling cancer signaling, one of their goals is to identify minimal sets of informative components that best reflect the state fo the cell and serve as molecular targets for diagnostics, imaging, and patient tailored treatment. As with all of systems biology, their research relies on an interdisciplinary approach that merges biology, chemistry, mathematics and computation / bioinformatics.
His work in cancer biology started with the discovery that hypoxia, a common feature of solid tumors, induces p53 protein levels, and that p53 deficient cells are less prone to undergo apoptosis in low oxygen conditions, conferring a survival advantage. These findings led to a model of hypoxia as a physiological selective force against apoptosis-competent cells in developing tumors, thus explaining the previously unaccounted for high frequency of p53 mutations in cancer. In computational biology, he developed an algorithm to identify potential autocrine signaling loops in cancer using gene expression microarray data. The algorithm integrates biological data (in this case, cognate ligand-receptor partners) into the analysis of raw gene expression data, and a number of leads from this method have been verified to play critical roles in cell signaling.
Recently, his lab has developed a mass-spectrometry based protocol for identifying tyrosine-phosphorylated proteins from cancer cell lysates. They are using this proteome-wide ‘phosphorylation profiling’ assay to identify the signaling pathways activated by various oncogenic initiating events (e.g. kinase mutations), and to elucidate the interconnectedness of classical signaling pathways into a more comprehensive signaling network. His lab is also analyzing large gene expression and proteomics datasets on human prostate cancer and mouse models of prostate cancer, and developing bioinformatic algorithms to identify conserved/critical oncogenic mechanisms through cross-species comparisons.
- Zimman A., Berliner J.A., Graeber T.G. “Phosphoproteomic analysis of aortic endothelial cells activated by oxidized phospholipids.” Methods Mol Biol. 2013;1000:53-69.
- Kidani Y., Elsaesser H., Hock M.B., Vergnes L., Williams K.J., Argus J.P., Marbois B.M., Komisopoulou E., Wilson E.B., Osborne T.F., Graeber T.G., Reue K., Brooks D.G., Bensinger S.J. “Sterol regulatory element-binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity.” Nat Immunol. 2013 May;14(5):489-99.
- Rohle D., Popovici-Muller J., Palaskas N., Turcan S., Grommes C., Campos C., Tsoi J., Clark O., Oldrini B., Komisopoulou E., Kunii K., Pedraza A., Schalm S., Silverman L., Miller A., Wang F., Yang H., Chen Y., Kernytsky A., Rosenblum M.K,. Liu W., Biller S.A., Su S.M., Brennan C.W., Chan T.A., Graeber T.G., Yen K.E., Mellinghoff I.K. “An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells.” Science. 2013 May 3;340(6132):626-30.
- Knight D.A., Ngiow S.F., Li M., Parmenter T., Mok S., Cass A., Haynes N.M., Kinross K., Yagita H., Koya R.C., Graeber T.G., Ribas A., McArthur G.A., Smyth M.J. “Host immunity contributes to the anti-melanoma activity of BRAF inhibitors.” J Clin Invest. 2013 Mar 1;123(3):1371-81.
- Teles R.M., Graeber T.G., Krutzik S.R., Montoya D., Schenk M., Lee D.J., Komisopoulou E., Kelly-Scumpia K., Chun R., Iyer S.S., Sarno E.N., Rea T.H., Hewison M., Adams J.S., Popper S.J., Relman D.A., Stenger S., Bloom B.R., Cheng G., Modlin R.L. “Type I interferon suppresses type II interferon-triggered human anti-mycobacterial responses.” Science. 2013 Mar 22;339(6126):1448-53.
- Williams K.J., Argus J.P., Zhu Y., Wilks M.Q., Marbois B.N., York A.G., Kidany Y., Pourzia A.L., Akhavan D., Lisiero D.N., Komisopoulou E., Henkin A.H., Soto H., Chamberlain B.T., Vergnes L., Jung M.E., Torres J.Z., Liau L.M., Chirstofk H.R., Prins R.M., Mischel P.S., Reue K., Graeber T.G., Bensinger S.J. “An Essential Requirement for the SCAP/SREBP Signaling Axis to Protect Cancer Cells from Lipotoxicity.” Cancer Res. 2013 May 1;73(9):2850-2862.
- Graham N.A., Tahmasian M., Kohli B., Komisopoulou E., Zhu M,. Vivanco I., Teitell M.A., Wu H., Ribas A., Lo R.S., Mellinghoff I.K., Mischel P.S., Graeber T.G. “Glucose deprivation activates a metabolic and signaling amplification loop leading to cell death.” Mol Syst Biol. 2012 Jun 26;8:859.
- Koya R.C., Mok S., Otte N., Blacketor K.J., Comin-Anduix B., Tumeh P.C., Minasayan A., Graham N.A., Graeber T.G., Chodon T., Ribas A. “BRAF inhibitor vemurafenib improves the antitumor activity of adoptive cell immunotherapy.” Cancer Res. 2012 Aug 15;72(16):3928-37.
- Schenk M., Krutzik S.R., Sieling P.A., Lee D.J., Teles R.M., Ochoa M.T., Komisopoulou E., Sarno E.N., Rea T.H., Graeber T.G., Kim S., Cheng G., Modlin R.L. “NOD2 triggers an interleukin-32-dependent human dendritic cell program in leprosy.” Nat Med. 2012 Mar 25;18(4):555-63.
- Tran L.M., Chang C.J., Plaisier S., Wu S., Dang J., Mischel P.S., Liao J.C., Graeber T.G., Wu H. “Determining PTEN functional status by network component deduced transcription factor activities.” PLoS One. 2012;7(2):e31053.