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reverse engineering and interrogation of regulatory networks in human malignancies

ICBP Centers. reverse engineering and interrogation of regulatory networks in human malignancies. Developmental. Transcriptional Interactions. POST-TRANSCRIPTIONAL INTERACTIONS. Zhao X et al. (2009) Dev Cell. 17(2):210-21. Mani KM et al. (2008) Mol Syst Biol. 4:169

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reverse engineering and interrogation of regulatory networks in human malignancies

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  1. ICBP Centers reverse engineering and interrogation of regulatory networks in human malignancies

  2. Developmental Transcriptional Interactions POST-TRANSCRIPTIONAL INTERACTIONS Zhao X et al. (2009) Dev Cell. 17(2):210-21. Mani KM et al. (2008) Mol Syst Biol. 4:169 Palomero T et al., Proc NatlAcadSci U S A 103, 18261 (Nov 28, 2006). Margolin AA et al., Nature Protocols; 1(2): 662-671 (2006) Margolin AA et al., BMC Bioinformatics 7 Suppl 1, S7 (2006). Basso K et al. (2005), Nat Genet.;37(4):382-90. (Apr. 2005) Basso et al. Immunity. 2009 May;30(5):744-52 Klein et al, Cancer Cell, 2010 Jan 19;17(1):28-40. Post-translational Interactions Master regulators and mechanism of action Wang K, Saito M, et al. (2009) Nat Biotechnol. 27(9):829-39 Zhao X et al. (2009) Dev Cell. 17(2):210-21. Wang K et al. (2009) Pac Symp Biocomput. 2009:264-75. Mani KM et al. (2008) Mol Syst Biol. 4:169 Wang K et al. (2006) RECOMB The CTD2 Network (2010), Nat Biotechnol. 2010 Sep;28(9):904-906. Floratos A et al. Bioinformatics. 2010 Jul 15;26(14):1779-80 Lefebvre C. et al (2010), Mol Syst. Biol, accepted with minor revision Carro MS et al. (2010) Nature 2010 Jan 21;463(7279):318-25 Mani K et al, (2008) Molecular Systems Biology, 4:169

  3. MARINa: Master Regulator Inference algorithm A Master Regulator is a gene that is necessary and/or sufficient to induce a specific cellular transformation or differentiation event. MRx Phenotype 1 (Normal) Phenotype 2 (Neoplastic) Repressed MRxTargets MRx ? Activated MRx Targets If MRx is a Master Regulator of Ph1→Ph2 transformation (and it is over-expressed in Ph2), then its regulated genes should distribute as follows (opposite if under-expressed): TF Regulon Activated MRx Targets Repressed MRxTargets Gene Expression Under-expressed in Ph2 vs. Ph1 Over-expressed in Ph2 vs. Ph1 • Carro, M. et al. (2010). "The transcriptional network for mesenchymal transformation of brain tumours." Nature463(7279): 318-325 • Lefebvre C. et al. (2009). "A Human B Cell Interactome Identifies MYB and FOXM1 as Regulators of Germinal Centers." Mol SystBiol, in press • Lim, W. et al. (2009). "Master Regulators Used As Breast Cancer Metastasis Classifier." Pac SympBiocomp14: 492-503

  4. Mouse immunohistochemistry Mouse Control Vector Stat3- C/EBPb- Stat3-/C/EBPb- Human

  5. Genetic Alterations account for 54% of Mes. tumors Mesenchymal Samples (174) Other (56) Gene KLHL9 Inferred via functional association of CNVs with change in mRNA levels, increase in CEBPD regulon activity TEAD3, ZFP36L2 Inferred via ARACNE and functional association of CNVs with change in mRNA levels CEBPb/d HMG20B, PTPRA Inferred via MINDY and functional association of CNVs Significantly Altered Odd Ratio = 5.405, p-value = 1.12e-6 MES signature Not Altered

  6. 2. Can we extrapolate GEP-Signature MoA from in vitro to in vivo? 5. Are Mouse models representative of human models? Concentration: Max non-toxic, based on published data Timepoints: 12h, 24h, 48h, 120h

  7. Acknowledgements • Califano Lab (Computational) • MukeshBansal, Ph.D. • ArchanaIyer, Ph.D. • Celine Lefebvre, Ph.D. • Wei Keat Lim, Ph.D. • AntoninaMitrofanova, Ph.D. • Jose’ Morales, Ph.D. • Paola Nicoletti, Ph.D. • PavelSumazin, Ph.D. • James Chen, (GRA) • Hua-Sheng Chu (GRA) • Wei-Jen Chung (GRA) • In Sock Jang (GRA) • William Shin (GRA) • Jiyang Yu (GRA) • Sean Zhu (GRA) • PradeepBandaru (Undergrad) • ManjunathKustagi (Programmer) • Software Development • ArisFloratos, Ph.D. (Exec. Director) • Ken Smith, Ph.D. • Min Yu, (Programmer) • Califano Lab Experimental • Gabrielle Rieckhof, Ph.D. (Exec Director) • Mariano Alvarez, Ph.D. • BrygidaBisikirska, Ph.D. • Hesed Kim • PreshaRajbhandari • Xuerui Yang, Ph.D. • JoridaCoku, (Technician) • Sergey Pampou, Ph.D. • DallaFavera Lab (CUMC) • Katia Basso • Ulf Klein • Iavarone & Lasorella Lab (CUMC) • Maria Stella Carro • Aldape Lab (MD Anderson) • Abate-Shen & Shen Lab (CUMC) • Alvaro AytesMeneses • Schreiber Lab (Broad Inst.) • Angela Koehler • AlyShamji • Michael White (UTSW) Funding Sources: NCI, caBIG, Roadmap, NIAID, SAIC Fredrickson

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