Dr. Thomas 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 aberrant cancer signaling and translating their discoveries to clinical applications. They have 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. In modeling cancer signaling, one of their goals is to identify minimal sets of informative components that best reflect the state of 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 combines biology, chemistry, mathematics and computation.
Selected Cancer-Related Publications:
Graham NA, Tahmasian M, Kohli B, Komisopoulou E, Zhu M, Vivanco I, Teitell MA, Wu H, Ribas A, Lo RS, Mellinghoff IK, Mischel PS, Graeber TG. Glucose deprivation activates a metabolic and signaling amplification loop leading to cell death. Mol Syst Biol. 2012 Jun 26;8:589.
Poulikakos PI, Persaud Y, Janakiraman M, Kong X, Ng C, Moriceau G, Shi H, Atefi M, Titz B, Gabay MT, Salton M, Dahlman KB, Tadi M, Wargo JA, Flaherty KT, Kelley MC, Misteli T, Chapman PB, Sosman JA, Graeber TG, Ribas A, Lo RS, Rosen N, Solit DB. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature. 2011 Dec 15;480(7377):387-90.
Rubbi L, Titz B, Brown L, Galvan E, Komisopoulou E, Chen SS, Low T, Tahmasian M, Skaggs B, Muschen M, Pellegrini M, Graeber TG. Global phosphoproteomics reveals crosstalk between Bcr-Abl and negative feedback mechanisms controlling Src signaling. Sci Signal. 2011 Mar 29;4(166):ra18.
Fang C, Wang Y, Vu NT, Lin WY, Hsieh YT, Rubbi L, Phelps ME, Muschen M, Kim YM, Chatziioannou AF, Tseng HR, Graeber TG. Integrated microfluidic and imaging platform for a kinase activity radioassay to analyze minute patient cancer samples. Cancer Res. 2010 Nov 1;70(21):8299-308. Epub 2010 Sep 13
Plaisier SB, Taschereau R, Wong JA, Graeber TG. Rank-rank hypergeometric overlap: identification of statistically significant overlap between gene-expression signatures. Nucleic Acids Res. 2010 Sep;38(17):e169. Epub 2010 Jul 21