Photo of Peter Sorger,  PhD

Peter Sorger, PhD

Harvard Medical School

Harvard Medical School

Peter Sorger, PhD

Harvard Medical School

EDUCATIONAL TITLES

  • Otto Krayer Professor of Systems Pharmacology, Systems Biology, Harvard Medical School

DF/HCC PROGRAM AFFILIATION

Research Abstract

Our lab aims to understand mechanisms controlling mammalian cell fate and that, when altered, cause cancer. We study the balance between extracellular factors that promote death and those that promote growth and survival with a focus on the spatio-temporal dynamics of receptor mediated apoptosis triggered by ligands such as TRAIL and growth-factor mediated mitogenesis trigged by EGF, insulin and insulin-like growth factors. We combine live-cell assays, multiplex-biochemistry and genetic manipulation with mathematical modeling of detailed cellular biochemistry (typically using differential equations), abstracted networks (using logical modeling) and state-phenotype relationships (using regression). Experiments are performed on cells grown in culture, knock-in and knock-out mice (of our own design) and increasingly primary human cells and tissue samples. We hope thereby to understand precisely how key signaling proteins regulate changes in cell physiology in the face of stochastic fluctuation, how signaling pathways change during oncogenic transformation and how drugs can best distinguish diseased v. normal tumors of different genotypes.

Publications

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  • Roux J, Hafner M, Bandara S, Sims JJ, Hudson H, Chai D, Sorger PK. Fractional killing arises from cell-to-cell variability in overcoming a caspase activity threshold. Mol Syst Biol 2015; 11:803. PubMed
  • Flusberg DA, Sorger PK. Surviving apoptosis: life-death signaling in single cells. Trends Cell Biol 2015. PubMed
  • Fallahi-Sichani M, Moerke NJ, Niepel M, Zhang T, Gray NS, Sorger PK. Systematic analysis of BRAFV600E melanomas reveals a role for JNK/c-Jun pathway in adaptive resistance to drug-induced apoptosis. Mol Syst Biol 2015; 11:797. PubMed
  • AlQuraishi M, Koytiger G, Jenney A, MacBeath G, Sorger PK. A multiscale statistical mechanical framework integrates biophysical and genomic data to assemble cancer networks. Nat Genet 2014; 46:1363-71. PubMed
  • Gujral TS, Chan M, Peshkin L, Sorger PK, Kirschner MW, MacBeath G. A noncanonical Frizzled2 pathway regulates epithelial-mesenchymal transition and metastasis. Cell 2014; 159:844-56. PubMed
  • Foijer F, Xie SZ, Simon JE, Bakker PL, Conte N, Davis SH, Kregel E, Jonkers J, Bradley A, Sorger PK. Chromosome instability induced by Mps1 and p53 mutation generates aggressive lymphomas exhibiting aneuploidy-induced stress. Proc Natl Acad Sci U S A 2014; 111:13427-32. PubMed
  • Duan Q, Flynn C, Niepel M, Hafner M, Muhlich JL, Fernandez NF, Rouillard AD, Tan CM, Chen EY, Golub TR, Sorger PK, Subramanian A, Ma'ayan A. LINCS Canvas Browser: interactive web app to query, browse and interrogate LINCS L1000 gene expression signatures. Nucleic Acids Res 2014. PubMed
  • Kallenberger SM, Beaudouin J, Claus J, Fischer C, Sorger PK, Legewie S, Eils R. Intra- and interdimeric caspase-8 self-cleavage controls strength and timing of CD95-induced apoptosis. Sci Signal 2014; 7:ra23. PubMed
  • Niepel M, Hafner M, Pace EA, Chung M, Chai DH, Zhou L, Muhlich JL, Schoeberl B, Sorger PK. Analysis of growth factor signaling in genetically diverse breast cancer lines. BMC Biol 2014; 12:20. PubMed
  • Paull EO, Carlin DE, Niepel M, Sorger PK, Haussler D, Stuart JM. Discovering causal pathways linking genomic events to transcriptional states using Tied Diffusion Through Interacting Events (TieDIE). Bioinformatics 2013; 29:2757-64. PubMed
  • Fallahi-Sichani M, Honarnejad S, Heiser LM, Gray JW, Sorger PK. Metrics other than potency reveal systematic variation in responses to cancer drugs. Nat Chem Biol 2013; 9:708-14. PubMed
  • Niepel M, Hafner M, Pace EA, Chung M, Chai DH, Zhou L, Schoeberl B, Sorger PK. Profiles of Basal and stimulated receptor signaling networks predict drug response in breast cancer lines. Sci Signal 2013; 6:ra84. PubMed
  • Marco E, Dorn JF, Hsu PH, Jaqaman K, Sorger PK, Danuser G. S. cerevisiae chromosomes biorient via gradual resolution of syntely between S phase and anaphase. Cell 2013; 154:1127-39. PubMed
  • Flusberg DA, Roux J, Spencer SL, Sorger PK. Cells surviving fractional killing by TRAIL exhibit transient but sustainable resistance and inflammatory phenotypes. Mol Biol Cell 2013; 24:2186-200. PubMed
  • Flusberg DA, Sorger PK. Modulating cell-to-cell variability and sensitivity to death ligands by co-drugging. Phys Biol 2013; 10:035002. PubMed
  • Koch Y, Wolf T, Sorger PK, Eils R, Brors B. Decision-tree based model analysis for efficient identification of parameter relations leading to different signaling states. PLoS ONE 2013; 8:e82593. PubMed
  • Thurber GM, Yang KS, Reiner T, Kohler RH, Sorger P, Mitchison T, Weissleder R. Single-cell and subcellular pharmacokinetic imaging allows insight into drug action in vivo. Nat Commun 2013; 4:1504. PubMed
  • Sorger PK, Schoeberl B. An expanding role for cell biologists in drug discovery and pharmacology. Mol Biol Cell 2012; 23:4162-4. PubMed
  • Spencer SL, Sorger PK. Measuring and modeling apoptosis in single cells. Cell 2011; 144:926-39. PubMed
  • Luckert K, Goetschel F, Sorger PK, Hecht A, Joos TO, Poetz O. Snapshots of protein dynamics and posttranslational modifications in one experiment - [beta]-catenin and its functions. Mol Cell Proteomics 2011. PubMed
  • Morris MK, Saez-Rodriguez J, Clarke DC, Sorger PK, Lauffenburger DA. Training signaling pathway maps to biochemical data with constrained fuzzy logic: quantitative analysis of liver cell responses to inflammatory stimuli. PLoS Comput. Biol. 2011; 7:e1001099. PubMed
  • Espelin CW, Goldsipe A, Sorger PK, Lauffenburger DA, de Graaf D, Hendriks BS. Elevated GM-CSF and IL-1beta levels compromise the ability of p38 MAPK inhibitors to modulate TNFalpha levels in the human monocytic/macrophage U937 cell line. Mol Biosyst 2010; 6:1956-72. PubMed
  • Alexopoulos LG, Saez Rodriguez J, Cosgrove BD, Lauffenburger DA, Sorger PK. Networks inferred from biochemical data reveal profound differences in TLR and inflammatory signaling between normal and transformed hepatocytes. Mol Cell Proteomics 2010; 9:1849-65. PubMed
  • Chen WW, Niepel M, Sorger PK. Classic and contemporary approaches to modeling biochemical reactions. Genes Dev 2010; 24:1861-75. PubMed
  • Cosgrove BD, Alexopoulos LG, Hang TC, Hendriks BS, Sorger PK, Griffith LG, Lauffenburger DA. Cytokine-associated drug toxicity in human hepatocytes is associated with signaling network dysregulation. Mol Biosyst 2010; 6:1195-206. PubMed
  • Lazzara MJ, Lane K, Chan R, Jasper PJ, Yaffe MB, Sorger PK, Jacks T, Neel BG, Lauffenburger DA. Impaired SHP2-mediated extracellular signal-regulated kinase activation contributes to gefitinib sensitivity of lung cancer cells with epidermal growth factor receptor-activating mutations. Cancer Res 2010; 70:3843-50. PubMed
  • Morris MK, Saez-Rodriguez J, Sorger PK, Lauffenburger DA. Logic-based models for the analysis of cell signaling networks. Biochemistry 2010; 49:3216-24. PubMed
  • Kim KA, Spencer SL, Albeck JG, Burke JM, Sorger PK, Gaudet S, Kim do H. Systematic calibration of a cell signaling network model. BMC Bioinformatics 2010; 11:202. PubMed
  • Prill RJ, Marbach D, Saez-Rodriguez J, Sorger PK, Alexopoulos LG, Xue X, Clarke ND, Altan-Bonnet G, Stolovitzky G. Towards a rigorous assessment of systems biology models: the DREAM3 challenges. PLoS ONE 2010; 5:e9202. PubMed
  • Spencer SL, Gaudet S, Albeck JG, Burke JM, Sorger PK. Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis. Nature 2009; 459:428-32. PubMed
  • Chen WW, Schoeberl B, Jasper PJ, Niepel M, Nielsen UB, Lauffenburger DA, Sorger PK. Input-output behavior of ErbB signaling pathways as revealed by a mass action model trained against dynamic data. Mol Syst Biol 2009; 5:239. PubMed
  • Saez-Rodriguez J, Alexopoulos LG, Epperlein J, Samaga R, Lauffenburger DA, Klamt S, Sorger PK. Discrete logic modelling as a means to link protein signalling networks with functional analysis of mammalian signal transduction. Mol Syst Biol 2009; 5:331. PubMed
  • Albeck JG, Burke JM, Spencer SL, Lauffenburger DA, Sorger PK. Modeling a snap-action, variable-delay switch controlling extrinsic cell death. PLoS Biol. 2008; 6:2831-52. PubMed
  • Albeck JG, Burke JM, Aldridge BB, Zhang M, Lauffenburger DA, Sorger PK. Quantitative analysis of pathways controlling extrinsic apoptosis in single cells. Mol Cell 2008; 30:11-25. PubMed
  • Janes KA, Gaudet S, Albeck JG, Nielsen UB, Lauffenburger DA, Sorger PK. The response of human epithelial cells to TNF involves an inducible autocrine cascade. Cell 2006; 124:1225-39. PubMed
  • Meraldi P, Draviam VM, Sorger PK. Timing and checkpoints in the regulation of mitotic progression. Dev Cell 2004; 7:45-60. PubMed
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