Anurag Singh, Ph.D.
Assistant Professor of Pharmacology and Medicine
Principal Investigator: Laboratory of Cancer Pharmacogenomics
Section of Hematology and Medical Oncology and Member, The Cancer Center
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.
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. PMC3291475. Abstract:.
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. PMC3204842. Full article .
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 Jul 23;5(11). PMC2917412. Full article: .
Singh A, Greninger P, Rhodes D, Koopman L, Violette S, Bardeesy N, Settleman J. A gene expression signature associated with “K-Ras addiction” reveals regulators of EMT and tumor cell survival. Cancer Cell. 2009 Jun 2;15(6):489-500. PMC 2743093. Full article: .
Chin TM, Quinlan MP,Singh A, Sequist LV, Lynch TJ, Haber DA, Sharma SV, Settleman J. Reduced Erlotinib sensitivity of epidermal growth factor receptor-mutant non-small cell lung cancer following cisplatin exposure: a cell culture model of second-line erlotinib treatment. Clin Cancer Res. 2008 Nov 1;14(22):6867-76. PMC2710881. Full article: .
Montagut C, Sharma SV, Shioda T, McDermott U, Ulman M, Ulkus LE, Dias-Santagata D, Stubbs H, Lee DY, Singh A, Drew L, Haber DA, Settleman J. Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Res . 2087 Jun 15;68(12):4853-61. PMC2692356. Full article: .
Campbell PM, Singh A, Williams FJ, Frantz K, Ulkü AS, Kelley GG, Der CJ. Genetic and pharmacologic dissection of Ras effector utilization in oncogenesis. Methods Enzymol. 2006; 407:195-217. Abstract: .
Singh A, Karnoub AE, Palmby TR, Lengyel E, Sondek J, Der CJ. Rac1b, a tumor associated, constitutively active Rac1 splice variant, promotes cellular transformation. Oncogene . 2004 Dec 16;23(58):9369-80. Abstract: .
Luquain C, Singh A, Wang L, Natarajan V, Morris AJ.Role of phospholipase D in agonist-stimulated lysophosphatidic acid synthesis by ovarian cancer cells. J Lipid Res . 2003 Oct;44(10):1963-75. Full Article: .