Dr. Singh’s laboratory studies deregulated signal transduction networks that contribute to the pathophysiology of lung, pancreatic and colon cancers. Adenocarcinomas that arise in these tissues frequently harbor mutations in the KRAS oncogene or components of the KRAS signaling pathway, such as BRAF or PI3K. The core KRAS signaling pathway has been very well characterized but the precise mechanisms governing tumor maintenance in KRAS mutant cancers remain to be fully elucidated. Through comparative whole genome expression profiling, Dr. Singh has previously shown that KRAS mutant cancers can be classified into discrete molecular subtypes based on a phenotypic dichotomy of KRAS oncogene “addiction” or dependency. He derived tissue or lineage-specific KRAS dependency gene expression signatures that reflect differing modes of KRAS-mediated signal transduction in lung versus pancreatic versus colon cancers. Therefore, Dr. Singh hypothesizes that context-specificity is critical in the analysis of KRAS signaling networks.
Current research in the Singh lab is focused on exploiting the various lineage-specific KRAS dependency signatures to reveal mechanisms by which oncogenic KRAS maintains tumor cell survival in a context-dependent manner. In colon cancer, Dr. Singh has identified the TGF-b activated kinase as a component of a Wnt-driven proinflammatory signaling network that promotes tumor cell survival in KRAS dependent colon cancer cells. In lung and pancreatic cancers, Dr. Singh’s lab is studying the molecular basis for the relationship between the developmental epithelial-mesenchymal transition (EMT) program and KRAS oncogene dependency, as well as a role for non-coding microRNAs in mediating this relationship. The lab uses computational methods to derive genomic profiles in cancer cell lines and human primary tumors. These profiles reveal differentially expressed gene modules that can be built into systems-level signaling network models of KRAS-driven tumor cell survival signaling. Components of these network models are functionally validated and tested by cell and molecular methodologies using cancer cell lines in vitro as well as xenografted tumors in mice.
Dr. Singh has expertise in:
1. Cell biology – mammalian cell culture, cell based assays, drug-dose response assays, luciferase reporter assays, immunofluorescence, laser confocal microscopy.
2. Functional genomics – cDNA microarray gene expression analyses, shRNA/RNAi assays, miRNA assays.
3. Molecular biology – PCR, qPCR, Northern blotting, cloning, Gateway cloning, mutagenesis, inducible gene expression (Tet system or ER fusion proteins).
4. Biochemistry – in vitro enzymatic/kinase assays, fluorescence-based small GTPase assays (GEFs/GAPs), IP and pull-down assays, signaling pathway analysis, Western blotting.
5. Mouse tumor models – transgenic mice and xenografted subcutaneous human tumors in immuno-compromised mice. In vivo pharmacology, IP drug delivery. Immunohistocytochemistry.
6. Research interests include:
a) signal transduction pathways in cancer progression, specifically the RAS signaling network.
b) identification of oncogenic kinases such as TAK1.
c) signaling network crosstalk e.g. RAS-Wnt.
- University of North Carolina at Chapel H, PhD
- Stony Brook University, BS
- Published on 9/21/2016
McNew KL, Whipple WJ, Mehta AK, Grant TJ, Ray L, Kenny C, Singh A. MEK and TAK1 Regulate Apoptosis in Colon Cancer Cells with KRAS-Dependent Activation of Proinflammatory Signaling. Mol Cancer Res. 2016 Dec; 14(12):1204-1216. PMID: 27655129.
- Published on 2/15/2016
Anderson NM, Li D, Peng HL, Laroche FJ, Mansour MR, Gjini E, Aioub M, Helman DJ, Roderick JE, Cheng T, Harrold I, Samaha Y, Meng L, Amsterdam A, Neuberg DS, Denton TT, Sanda T, Kelliher MA, Singh A, Look AT, Feng H. The TCA cycle transferase DLST is important for MYC-mediated leukemogenesis. Leukemia. 2016 Jun; 30(6):1365-74. PMID: 26876595.
- Published on 2/12/2015
Javaid S, Zhang J, Smolen GA, Yu M, Wittner BS, Singh A, Arora KS, Madden MW, Desai R, Zubrowski MJ, Schott BJ, Ting DT, Stott SL, Toner M, Maheswaran S, Shioda T, Ramaswamy S, Haber DA. MAPK7 Regulates EMT Features and Modulates the Generation of CTCs. Mol Cancer Res. 2015 May; 13(5):934-43. PMID: 25678598.
- Published on 3/19/2014
Wang M, Kern AM, Hülskötter M, Greninger P, Singh A, Pan Y, Chowdhury D, Krause M, Baumann M, Benes CH, Efstathiou JA, Settleman J, Willers H. EGFR-mediated chromatin condensation protects KRAS-mutant cancer cells against ionizing radiation. Cancer Res. 2014 May 15; 74(10):2825-34. PMID: 24648348.
- Published on 12/13/2012
Corcoran RB, Cheng KA, Hata AN, Faber AC, Ebi H, Coffee EM, Greninger P, Brown RD, Godfrey JT, Cohoon TJ, Song Y, Lifshits E, Hung KE, Shioda T, Dias-Santagata D, Singh A, Settleman J, Benes CH, Mino-Kenudson M, Wong KK, Engelman JA. Synthetic lethal interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS mutant cancer models. Cancer Cell. 2013 Jan 14; 23(1):121-8. PMID: 23245996.
- Published on 2/17/2012
Singh A, Sweeney MF, Yu M, Burger A, Greninger P, Benes C, Haber DA, Settleman J. TAK1 inhibition promotes apoptosis in KRAS-dependent colon cancers. Cell. 2012 Feb 17; 148(4):639-50. PMID: 22341439.
- Published on 10/10/2011
Ebi H, Corcoran RB, Singh A, Chen Z, Song Y, Lifshits E, Ryan DP, Meyerhardt JA, Benes C, Settleman J, Wong KK, Cantley LC, Engelman JA. Receptor tyrosine kinases exert dominant control over PI3K signaling in human KRAS mutant colorectal cancers. J Clin Invest. 2011 Nov; 121(11):4311-21. PMID: 21985784.
- Published on 7/23/2010
Singh A, Boyer JL, Der CJ, Zohn IE. Transformation by a nucleotide-activated P2Y receptor is mediated by activation of Galphai, Galphaq and Rho-dependent signaling pathways. J Mol Signal. 2010; 5(11).
- Published on 6/7/2010
Singh A, Settleman J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene. 2010 Aug 26; 29(34):4741-51. PMID: 20531305.
- Published on 9/1/2009
Singh A, Settleman J. Oncogenic K-ras "addiction" and synthetic lethality. Cell Cycle. 2009 Sep 1; 8(17):2676-7. PMID: 19690457.
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