Dr. Steve Cole's laboratory studies how hormones regulate human and viral genomes. His studies show how stress suppresses immune system function and enhances activity of the HIV and cancer-causing viruses such as Kaposi's Sarcoma Herpes Virus. His laboratory also develops new mathematical tools for analyzing complex gene networks.
Cole's research focuses on the role of cAMP/PKA signaling in regulating global patterns of gene expression. A broad array of viral genomes respond to this cellular signaling pathway, and Cole's lab has mapped several points of interaction between PKA signaling and viral replication cycles. In the case of HIV-1, PKA upregulates the co-receptors CCR5 and CXCR4, induces cellular transcription factors to interact with the viral LTR and suppresses antiviral Type I interferons. In the case of the Kaposi's Sarcoma Herpes Virus (KSHV/HHV-8), PKA upregulates transcription of the key viral transcription factor RTA and post-translationally modifies its trans-activating capacity. Similar mechanisms have been identified for HCMV and HSV-1 and -2. Cole and his colleagues are now evaluating pharmacologic kinase modulators and gene therapeutic manipulation of PKA and downstream transcription factors. These principles have already been applied to developing novel vector-born adjuvants to enhance vaccine-induced cellular immune responses.
In the human genome, PKA mediates hormonal control of ~5,000 genes, but the teleologic principle defining its scope is poorly understood. Cole and associates have combined the mathematics of complex systems with principles from linguistics to identify the biological "meaning" of signal transduction pathways. For example, NF- B "means" inflammation, but the meaning of other signaling pathways is less clear and highly "contextual" (varies with cell type or activity of other signaling pathways). The researchers have developed a series of bioinformatics tools for mapping broad patterns of change in gene expression, inferring the up-stream signaling processes that drive those changes, and identifying combinatorial effects of genes and transcription factors that differ from their separate individual effects. The overarching aim of this work is to elevate genomic analyses out of the crowded field of ~30,000 genes and into a smaller set of abstract principles corresponding to signal transduction pathways and biological response themes.
Selected Cancer-Related Publications:
Cole SW, Sood AK, Cole SW. Molecular pathways: beta-adrenergic signaling in cancer. Clin Cancer Res. 2012 Mar 1;18(5):1201-6. Epub 2011 Dec 20
Lamkin DM, Sloan EK, Patel AJ, Chiang BS, Pimentel MA, Ma JC, Arevalo JM, Morizono K, Cole SW. Chronic stress enhances progression of acute lymphoblastic leukemia via Beta-adrenergic signaling. Brain Behav Immun. 2012 May;26(4):635-41. Epub 2012 Jan 25
Lutgendorf SK, Degeest K, Dahmoush L, Farley D, Penedo F, Bender D, Goodheart M, Buekers TE, Mendez L, Krueger G, Clevenger L, Lubaroff DM, Sood AK, Cole SW. Social isolation is associated with elevated tumor norepinephrine in ovarian carcinoma patients. Brain Behav Immun. 2011 Feb;25(2):250-5. Epub 2010 Oct 16
Cole SW, Arevalo JM, Takahashi R, Sloan EK, Lutgendorf SK, Sood AK, Sheridan JF, Seeman TE. Computational identification of gene-social environment interaction at the human IL6 locus. Proc Natl Acad Sci U S A. 2010 Mar 23;107(12):5681-6. Epub 2010 Feb 22
Sloan EK, Priceman SJ, Cox BF, Yu S, Pimentel MA, Tangkanangnukul V, Arevalo JM, Morizono K, Karanikolas BD, Wu L, Sood AK, Cole SW. The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Res. 2010 Sep 15;70(18):7042-52. Epub 2010 Sep 7