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:
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.
Lutgendorf SK, DeGeest K, Sung CY, Arevalo JM, Penedo F, Lucci J 3rd, Goodheart M, Lubaroff D, Farley DM, Sood AK, Cole SW. Depression, social support, and beta-adrenergic transcription control in human ovarian cancer. Brain Behav Immun. 2009 Feb;23(2):176-83. Epub 2008 Jun 11.
Thaker PH, Han LY, Kamat AA, Arevalo JM, Takahashi R, Lu C, Jennings NB, Armaiz-Pena G, Bankson JA, Ravoori M, Merritt WM, Lin YG, Mangala LS, Kim TJ, Coleman RL, Landen CN, Li Y, Felix E, Sanguino AM, Newman RA, Lloyd M, Gershenson DM, Kundra V, Lopez-Berestein G, Lutgendorf SK, Cole SW, Sood AK. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat Med. 2006; 12(8): 939-44.
Chang M, Brown HJ, Collado-Hidalgo A, Arevalo JM, Galic Z, Symensma TL, Tanaka L, Deng H, Zack JA, Sun R. beta-Adrenoreceptors reactivate Kaposi's sarcoma-associated herpesvirus lytic replication via PKA-dependent control of viral RTA. J Virol. 2005; 79(21): 13538-47.
Bower JE, Ganz PA, Aziz N, Fahey JL. T-cell homeostasis in breast cancer survivors with persistent fatigue. J Natl Cancer Inst. 2003; 95(15): 1165-8.