Cancer is a complex disease which is often characterized by deregulated intracellular signal transduction. Our long-term goal is to gain insight into signal transduction pathways underlying cancer cell growth and death.
Currently, the Eliopoulos' laboratory engages in two specific areas of research:
1. Regulation of TNF Receptor-associated factor (TRAF) signal transduction.
TRAFs are adaptor molecules which link various receptors and viral proteins to the activation of oncogenic and pro-inflammatory signaling pathways, such as NF-kB and MAPKs. A major effort in the lab is directed at the identification of novel components of the CD40 and TNF receptor/TRAF signaling networks.
2. The role of inflammatory signaling pathways in carcinogenesis.
Epidemiological, clinical and experimental data suggest that a number of human malignancies can be attributed to toxic agents and irritants or to persistent infections of viral or bacterial etiology which cause chronic inflammatory imbalance in the affected tissue. We utilize chemical-induced carcinogenesis protocols in animal models to dissect the role of the various cell types present in the tumor and analyze the signals exchanged between these cells. The practical benefits of this research will assist in the improved design of novel anti-cancer therapeutics and diagnostic tools to address prevention, early detection and improved management of human cancer.
Gkirtzimanaki K, Gkouskou KK, Oleksiewicz U, Nikolaidis G, Vyrla D, Liontos M, Pelekanou V, Kanellis DC, Evangelou K, Stathopoulos EN, Field JK, Tsichlis PN, Gorgoulis V, Liloglou T, Eliopoulos AG. (2013) TPL2 kinase is a suppressor of lung carcinogenesis. Proc Natl Acad Sci U S A. 110: E1470–E1479.
Knox PG, Davies CC, Ioannou M, Eliopoulos AG. (2011) The death kinase RIP1 links the immunoregulatory CD40 receptor to apoptotic signaling in carcinomas. J. Cell Biol. 192: 391-9.
Moschonas A, Kouraki M, Knox PG, Thymiakou E, Kardassis D, Eliopoulos AG. (2008) CD40 induces antigen transporter and immunoproteasome gene expression in carcinomas via the coordinated action of NF-κB and of NF-κB mediated de novo synthesis of IRF-1. Mol Cell Biol. 28: 6208-6222.
Eliopoulos AG. (2008) 'Make and Brake' in signaling (Perspective). Science 321:648-649.
Eliopoulos AG, Wang C-C, Dumitru CD, Tsichlis PN. (2003) Tpl2 transduces CD40 and TNF receptor signals that activate ERK and regulate immunoglobulin production. EMBO J 22: 3855-3864.
Recent Publications (2000 – present)
Doxaki C, Kampranis SC, Eliopoulos AG, Spilianakis C, Tsatsanis C. Coordinated Regulation of miR-155 and miR-146a Genes during Induction of Endotoxin Tolerance in Macrophages. J Immunol. 2015; 195(12):5750-61.
Apidianakis, Y, Eliopoulos, AG. A holo'ome approach in colon cancer: we change as we age. EMBO Rep. 2015; 16(10):1239-40.
Kanellis, DC; Bursac, S; Tsichlis, PN; Volarevic, S; Eliopoulos, AG, Physical and functional interaction of the TPL2 kinase with nucleophosmin. Oncogene. 2015; 34(19)
Vlahava, VM; Eliopoulos, AG; Sourvinos, G, CD40 ligand exhibits a direct antiviral effect on Herpes Simplex Virus type-1 infection via a PI3K-dependent, autophagy-independent mechanism, Cellular Signalling. 2015; 27(6): 1253-1263
Kanellis, DC; Bursac, S; Tsichlis, PN; Volarevic, S; Eliopoulos, AG, Physical and functional interaction of the TPL2 kinase with nucleophosmin. Oncogene. 2015; 34(19):2516-26.
Papanikolaou, N; Pavlopoulos, GA; Pafilis, E; Theodosiou, T; Schneider, R; Satagopam, VP; Ouzounis, CA; Eliopoulos, AG; Promponas, VJ; Iliopoulos, I, BioTextQuest(+): a knowledge integration platform for literature mining and concept discovery, Bioinformatics. 2014; 30(22): 3249-3256
Liljenfeldt, L; Gkirtzimanaki, K; Vyrla, D; Svensson, E; Loskog, ASI; Eliopoulos, AG, Enhanced therapeutic anti-tumor immunity induced by co-administration of 5-fluorouracil and adenovirus expressing CD40 ligand, Cancer Immunology Immunotherapy. 2014; 63(3): 273-282
Miliara, S; Gkouskou, KK; Sharp, TV; Eliopoulos, AG, SUMOylation Is Required for Optimal TRAF3 Signaling Capacity, PLOS ONE. 2013; 8(11): e80470
Gkirtzimanaki K, Gkouskou KK, Oleksiewicz U, Nikolaidis G, Vyrla D, Liontos M, Pelekanou V, Kanellis DC, Evangelou K, Stathopoulos EN, Field JK, Tsichlis PN, Gorgoulis V, Liloglou T, Eliopoulos AG. TPL 2 kinase is a suppressor of lung carcinogenesis. Proc Natl Acad Sci U S A. 2013; 110: E1470–E1479.
Moschonas A, Ioannou M, Eliopoulos AG. CD40 stimulates a "feed-forward" NF- κ B-driven molecular pathway that regulates IFN- β expression in carcinoma cells. J. Immunol. 2012; 188 : 5521-7.
Serebrennikova OB, Tsatsanis C, Mao C, Gounaris E, Ren W, Siracusa LD, Eliopoulos AG, Khazaie K, Tsichlis PN. Tpl2 ablation promotes intestinal inflammation and tumorigenesis in Apcmin mice by inhibiting IL-10 secretion and regulatory T-cell generation. Proc. Natl. Acad. Sci. USA 2012; 109(18):E1082-91.
Diaconu I, Cerullo V, Hirvinen ML, Escutenaire S, Ugolini M, Pesonen SK, Bramante S, Parviainen S, Kanerva A, Loskog AS, Eliopoulos AG, Pesonen S, Hemminki A. Immune response is an important aspect of the antitumor effect produced by a CD40L-encoding oncolytic adenovirus. Cancer Res. 2012; 72(9):2327-38.
Sideridou M, Zakopoulou, R, Evangelou K, Liontos M, Kotsinas A, Rampakakis E, Gagos S, Kahata K, Grabusic K, Gkouskou K, Trougkakos I, Kolettas E, Georgakilas AG, Volarevic S, Eliopoulos AG, Zannis-Hadjopoulos M, Moustakas A and Gorgoulis VG: Cdc6 acts as a “switch” at the E-cadherin locus linking transcriptional repression to activation of replication. J. Cell Biol. 2011, 195: 1123-1140.
Knox PG, Davies CC, Ioannou M & Eliopoulos AG: The death kinase RIP1 links the immunoregulatory CD40 receptor to apoptotic signaling in carcinoma. J. Cell Biol. 2011, 192: 391-9.
Mavroudi I, Papadaki V, Pyrovolaki K, Katonis P, Eliopoulos AG, Papadaki HA: The CD40/CD40 ligand interactions exert pleiotropic effects on bone marrow granulopoiesis. J Leukoc Biol. 2011; 89(5):771-83.
Filippakis H, Dimitropoulou P, Eliopoulos AG, Spandidos DA, Sourvinos G: The enhanced host-cell permissiveness of human cytomegalovirus is mediated by the Ras signaling pathway. Biochim Biophys Acta. 2011 1813(10):1872-82΄.
Vougioukalaki M, Kanellis DC, Gkouskou K, Eliopoulos AG: Tpl2 kinase signal transduction in inflammation and cancer. Cancer Lett. 2011;304(2):80-9. (Review article).
Mitchell K, Svenson KB, Longmate WM, Gkirtzimanaki K, Sadej R,Wang X, Zhao J, Eliopoulos AG, Berditchevski F, and DiPersio CM: Suppression of integrin α 3 β 1 in breast cancer cells reduces COX-2 gene expression and inhibits tumorigenesis, invasion, and crosstalk to endothelial cells. Cancer Res. 70:6359-67, 2010.
Vardouli L, Lindqvist C, Vlahou K, Loskog AS, Eliopoulos AG: Adenovirus delivery of human CD40 ligand gene confers direct therapeutic effects on carcinomas. Cancer Gene Ther. 2009, 16: 848-60.
Oakley F, Teoh V, Ching-A-Sue G, Bataller R, Colmenero J, Jonsson JR, Eliopoulos AG , Watson MR, Manas D, Mann DA. Angiotensin II Activates IkappaB kinase Phosphorylation of RelA at Ser(536) to Promote Myofibroblast Survival and Liver Fibrosis. Gastroenterology. 2009, 136: 2334-2344.
Pyrovolaki K, Mavroudi I, Sidiropoulos P, Eliopoulos AG , Boumpas DT, Papadaki HA: Increased expression of CD40 on bone marrow CD34 + hematopoietic progenitor cells in patients with systemic lupus erythematosus: Contribution to Fas-mediated apoptosis. Arthritis Rheum. 2009; 60:543-52.
Eliopoulos AG: ‘Make and Brake' in signaling (Perspective) . Science 2008 ; 321 : 648-649.
Moschonas A, Kouraki M, Knox PG, Thymiakou E, Kardassis D & Eliopoulos AG : CD40 induces antigen transporter and immunoproteasome gene expression in carcinomas via the coordinated action of NF- kB and of NF- kB mediated de novo synthesis of IRF -1. Mol. Cell. Biol. 2008, 28: 6208-6222.
Stewart R, Wei W, Challa A, Armitage RJ, Arrand JR, Rowe M, Young LS, Eliopoulos AG , and Gordon J: CD154 tone sets the signaling pathways and transcriptome generated in model CD40-pluricompetent L3055 Burkitt's lymphoma cells. J. Immunol. 2007 ; 179: 2705-2712.
Eliopoulos AG , Das S, Tsichlis PN. The tyrosine kinase SYK regulates TPL 2 activation signals. J Biol Chem. 2006; 281: 1371-1380.
Davies CC, Mak TW, Young LS, Eliopoulos AG . TRAF6 is required for TRAF2-dependent CD40 signal transduction in nonhemopoietic cells. Mol Cell Biol. 2005; 25:9806-19.
Baxendale AJ, Dawson CW, Stewart SE, Mudaliar V, Reynolds G, Gordon J, Murray PG, Young LS, Eliopoulos AG . Constitutive activation of the CD40 pathway promotes cell transformation and neoplastic growth. Oncogen e 2005 24:7913-7923.
Das S, Cho J, Lambertz I, Kelliher MA, Eliopoulos AG , Du K, Tsichlis PN. Tpl2/Cot signals activate ERK, JNK and NF-kappa B in a cell type and stimulus-specific manner. J Biol Chem. 2005; 280:23748-57.
Papadaki HA, Stamatopoulos K, Damianaki A, Gemetzi C, Anagnostopoulos A, Papadaki T, Eliopoulos AG , Eliopoulos GD. Activated T-lymphocytes with myelosuppressive properties in patients with chronic idiopathic neutropenia. Br J Haematol. 2005; 128:863-76.
Cerimele F, Battle T, Lynch R, Frank DA, Murad E, Cohen C, Macaron N, Sixbey J, Smith K, Watnick RS, Eliopoulos A , Shehata B, Arbiser JL. Reactive oxygen signaling and MAPK activation distinguish Epstein-Barr Virus (EBV)-positive versus EBV-negative Burkitt's lymphoma. Proc. Natl. Acad. Sci. U S A. 2005; 102:175-179.
Hill SC , Youde SJ , Man S , Teale GR , Baxendale AJ , Hislop A , Davies CC , Luesley DM , Blom AM , Rickinson AB , Young LS and Eliopoulos AG . Activation of CD 40 in cervical carcinoma cells facilitates cytotoxic T lymphocyte responses and augments chemotherapy - induced apoptosis . J. Immunol. 2005; 174: 41-50.
Davies CC, Bem D, Young LS and Eliopoulos AG . NF- k B overrides the apoptotic program of TNF receptor 1 but not CD40 in carcinoma cells. Cell. Signal. 2005; 17: 729-738.
Eliopoulos AG and Young LS. The role of CD40 in the pathogenesis and treatment of cancer. Curr. Opinion Pharmacol. 2004; 4: 360-367.
Carragher D, Johal R, Button A, White A, Eliopoulos AG , Jenkinson E, Anderson G, Caamaño JH. A stroma-derived defect in NF- k B2 -/- mice causes impaired lymph node development and lymphocyte recruitment. J Immunol 2004; 173: 2271-2279.
Li HM, Zhuang Z, Wang Q, Wang X, Wong HL, Feng H, Jin D, Ling MT, Wong YC, Eliopoulos AG , Young LS, Huang D, Tsao SW. Epstein-Barr Virus Latent Membrane Protein 1 (LMP1) up-regulates Id1 expression in nasopharyngeal epithelial cells. Oncogene 2004; 23: 4488-4494.
Davies C, Mason J., Wakelam MJO, Young LS, Eliopoulos AG . Inhibition of PI3K and ERK MAPK-regulated protein synthesis unveils the pro-apoptotic properties of CD40 ligation in carcinoma cells. J Biol Chem 2004; 279: 1110-1019.
Eliopoulos AG , Caamano JH, Flavell J, Reynolds GM, Murray PG, Poyet J-L, Young LS. The Epstein-Barr virus-encoded latent infection membrane protein 1 (LMP1) regulates the processing of p100 NF- kB2 to p52 via an IKKγ /NEMO-independent signaling pathway. Oncogene 2003; 22: 7557-7569 (commentary publication accompanies this paper).
Eliopoulos AG , Wang C-C, Dumitru CD, Tsichlis PN. Tpl2 transduces CD40 and TNF receptor signals that activate ERK and regulate immunoglobulin production. EMBO J 2003; 22: 3855-3864.
Hewison M, Freeman L, Hughes SV, Evans KN, Bland R, Eliopoulos AG , Kilby M, Moss PAH, Chakraverty R. D ifferential regulation of vitamin D receptor and its ligand in human monocyte-derived dendritic cells. J Immunol 2003; 170: 5382-5390.
Eliopoulos AG , Waites ER, Blake SM, Davies C, Murray P, Young LS. TRAF1 is a critical regulator of JNK signaling by the TRAF-binding domain of the Epstein-Barr virus-encoded latent infection membrane protein 1 but not CD40. J Virology 2003; 77: 1316-1328.
Papadaki HA, Eliopoulos AG , Kosteas T, Gemetzi C, Damianaki A, Koutala H, Bux J, Eliopoulos GD. Impaired granulocytopoiesis in patients with chronic idio-pathic neutropenia is associated with increased apoptosis of bone marrow myeloid progenitor cells. Blood 2003; 101: 2591-2600.
Knox PG, Milner AE, Green NK, Eliopoulos AG , Young LS. Inhibition of metal-loproteinase cleavage enhances the cytotoxicity of Fas ligand. J Immunol 2003; 170: 677-685.
Dawson CW, Tramountanis G, Eliopoulos AG , Young LS. Epstein-Barr virus latent membrane protein 1 (LMP1) activates the phosphatidylinositol 3-kinase/Akt pathway to promote cell survival and induce actin filament remodeling. J Biol Chem 2003; 278: 3694-3704.
Eliopoulos AG , Dumitru CD, Wang CC, Cho J, Tsichlis PN. Induction of COX -2 by LPS in macrophages is regulated by Tpl2-dependent CREB activation signals. EMBO J 2002; 21: 4831-4840.
Challa A # , Eliopoulos AG # , Holder MJ, Burguete AS, Pound JD, Chamba A, Grafton G, Armitage RJ, Gregory CD, Martinez-Valdez H, Young L, Gordon J. Population depletion activates autonomous CD154-dependent survival in biopsy like Burkitt lymphoma cells. Blood 2002; 99: 3411-3418 . (# Equal contribution)
Milner AE, Palmer DH, Hodgkin EA, Eliopoulos AG , Knox PG, Poole CJ, Kerr DJ, Young LS Induction of apoptosis by chemotherapeutic drugs: the role of FADD in activation of caspase-8 and synergy with death receptor ligands in ovarian carcinoma cells. Cell Death Differ 2002; 9: 287-300.
Eliopoulos AG , Davies C, Blake SS, Murray P, Najafipour S, Tsichlis PN, Young LS. The oncogenic protein kinase Tpl-2/Cot contributes to Epstein-Barr virus-encoded latent infection membrane protein 1-induced NF-kappaB signaling down-stream of TRAF2. J Virology 2002; 76: 4567-4579.
Afford SC, Ahmed-Choudhury J, Randhawa S, Russell C, Youster J, Crosby HA, Eliopoulos AG , Hubscher SG, Young LS, Adams DH. CD40 activation-induced, Fas-dependent apoptosis and NF-kappaB/AP-1 signaling in human intrahepatic bi-liary epithelial cells. FASEB J 2001; 15: 2345-2354 .
Blake SM, Eliopoulos AG , Dawson CW, Young LS. The transmembrane domains of the EBV-encoded latent membrane protein 1 (LMP1) variant CAO regulate enhanced signalling activity. Virology 2001; 282: 278-287 .
Eliopoulos AG , Young LS. LMP1 structure and signal transduction. Semin Cancer Biol 2001; 11: 435-444.
Eliopoulos AG , Davies C, Knox PG, Gallagher NJ , Afford SC, Adams DH, Young LS. CD40 induces apoptosis in carcinoma cells through activation of cy-totoxic ligands of the tumor necrosis factor superfamily. Mol Cell Biol 2000; 20: 5503-5515.
Dawson CW, Eliopoulos AG , Blake SM, Barker R, Young LS. Identification of functional differences between prototype Epstein-Barr virus-encoded LMP1 and a nasopharyngeal carcinoma-derived LMP1 in human epithelial cells. Virology 2000; 272: 204-217.