Main Research Directions/Ongoing Research Activities
The exposome and human health (P. Georgiadis, S.A. Kyrtopoulos)
Investigation of the role of the «Environment» in the etiology of disease and morbidity in humans.
The emerging concept of the “exposome” refers to the totality of the exposures suffered by an individual, coming from all sources, including the environment, food as well as psycho-social components, from conception onwards. One of the key tools for the development and application of the exposome concept is the use of global sets of biomarkers (-omics) as generic measures of the internal exposome and disease risk. We focus on the exploration of the role of exposure to environmental toxic agents as a modulator of the epigenetic mechanisms of control of gene expression and hence of adverse health outcomes such as cancer and neurodevelopmental disorders. Cohort-based field studies as well as in vitro and in vivo studies are being implemented.
Georgiadis, P., Gavriil, M., Rantakokko, P., Ladoukakis, E., Botsivali, M., Kelly, R.S., Bergdahl, I.A., Kiviranta, H., Vermeulen, R.C.H., Spaeth, F., Hebbels, D.G.A.J., Kleinjans, J.C.S., de Kok, T.M.C.M., Palli, D., Vineis, P., Kyrtopoulos, S.A., DNA methylation profiling implicates exposure to PCBs in the pathogenesis of B-cell chronic lymphocytic leukemia. Environment international, 2019, 126, 24–36. https://doi.org/10.1016/j.envint.2019.01.068
Ek, W.E., Tobi, E.W., Ahsan, M., Lampa, E., Ponzi, E., Kyrtopoulos, S.A., Georgiadis, P., Lumey, L.H., Heijmans, B.T., Botsivali, M., Bergdahl, I.A., Karlsson, T., Rask-Andersen, M., Palli, D., Ingelsson, E., Hedman, A.K., Nilsson, L.M., Vineis, P., Lind, L., Flanagan, J.M., Johansson, A., Tea and coffee consumption in relation to DNA methylation in four European cohorts. Human Molecular Genetics, 2017, 26, 3221–3231. https://doi.org/10.1093/hmg/ddx194
Georgiadis, P., Liampa, I., Hebels, D.G., Krauskopf, J., Chatziioannou, A., Valavanis, I., de Kok, T.M.C.M., Kleinjans, J.C.S., Bergdahl, I.A., Melin, B., Spaeth, F., Palli, D., Vermeulen, R.C.H., Vlaanderen, J., Chadeau-Hyam, M., Vineis, P., Kyrtopoulos, S.A., Gottschalk, R., van Leeuwen, D., Timmermans, L., Botsivali, M., Bendinelli, B., Kelly, R., Portengen, L., Saberi-Hosnijeh, F., Hallmans, G., Lenner, P., Keun, H.C., Siskos, A., Athersuch, T.J., Kogevinas, M., Stephanou, E.G., Myridakis, A., Fazzo, L., Santis, M.D., Comba, P., Kiviranta, H., Rantakokko, P., Airaksinen, R., Ruokojärvi, P., Gilthorpe, M., Fleming, S., Fleming, T., Tu, Y.-K., Jonsson, B., Lundh, T., Chen, W.J., Lee, W.-C., Hsiao, C.K., Chien, K.-L., Kuo, P.-H., Hung, H., Liao, S.-F., Evolving DNA methylation and gene expression markers of B-cell chronic lymphocytic leukemia are present in pre-diagnostic blood samples more than 10 years prior to diagnosis. BMC Genomics, 2017, 18. https://doi.org/10.1186/s12864-017-4117-4
Georgiadis, P., Hebels, D.G., Valavanis, I., Liampa, I., Bergdahl, I.A., Johansson, A., Palli, D., Chadeau-Hyam, M., Chatziioannou, A., Jennen, D.G.J., Krauskopf, J., Jetten, M.J., Kleinjans, J.C.S., Vineis, P., Kyrtopoulos, S.A., Gottschalk, R., van Leeuwen, D., Timmermans, L., de Kok, T.M.C.M., Botsivali, M., Bendinelli, B., Kelly, R., Vermeulen, R., Portengen, L., Saberi-Hosnijeh, F., Melin, B., Hallmans, G., Lenner, P., Keun, H.C., Siskos, A., Athersuch, T.J., Kogevinas, M., Stephanou, E.G., Myridakis, A., Fazzo, L., De Santis, M., Comba, P., Kiviranta, H., Rantakokko, P., Airaksinen, R., Ruokojärvi, P., Gilthorpe, M., Fleming, S., Fleming, T., Tu, Y.-K., Jonsson, B., Lundh, T., Chen, W.J., Lee, W.-C., Kate Hsiao, C., Chien, K.-L., Kuo, P.-H., Hung, H., Liao, S.-F., Omics for prediction of environmental health effects: Blood leukocyte-based cross-omic profiling reliably predicts diseases associated with tobacco smoking. Scientific Reports, 2016, 6, 20544. https://doi.org/10.1038/srep20544
Hebels, D.G.A.J., Georgiadis, P., Keun, H.C., Athersuch, T.J., Vineis, P., Vermeulen, R., Portengen, U., Bergdahl, I.A., Hallmans, G., Palli, D., Bendinelli, B., Krogh, V., Tumino, R., Sacerdote, C., Panico, S., Kleinjans, J.C.S., de Kok, T.M.C.M., Smith, M.T., Kyrtopoulos, S.A., Performance in omics analyses of blood samples in long-term storage: Opportunities for the exploitation of existing biobanks in environmental health research. Environmental Health Perspectives, 2013, 121, 480–487. https://doi.org/10.1289/ehp.1205657
Nutrition, Gut microbiome and Cancer prevention (V. Pletsa, P. Georgiadis)
Investigation of the role of nutrition and gut microbiome in wellbeing as well as in the etiology of disease and morbidity in humans
The study of the biological effects of neutraceuticals at cellular level provides the molecular basis for their anti-tumor function and helps to establish the platform for generating more potent chemopreventive and even chemotherapeutic agents. Weaim at unravelling the role of neutraceuticals in cancer prevention and wellbeing in order to develop novel functional products of high added value through exploiting the Greek biodiversity. Supported by and building on the FUNglucan project (2018-2021) and through applying holistic approaches such as NMR Metabolomics and Next Generation Sequencing, we aim at identifying dietary factors with enhanced prebiotic activity in view of the development of novel food products which promote health and quality of life, of the elderly in particular. In vitro, in vivo, ex vivoas well as clinical intervention studies are being implemented.
Koutrotsios, G., Patsou, M., Mitsou, E.K., Bekiaris, G., Kotsou, M., Tarantilis, P.A., Pletsa, V., Kyriacou, A., Zervakis, G.I., Valorization of olive by-products as substrates for the cultivation of ganoderma lucidum and pleurotus ostreatus mushrooms with enhanced functional and prebiotic properties. Catalysts, 2019, 9. https://doi.org/10.3390/catal9060537
Turunen, K.T., Pletsa, V., Georgiadis, P., Triantafillidis, J.K., Karamanolis, D., Kyriacou, A., Impact of beta-glucan on the Fecal Water Genotoxicity of Polypectomized Patients. NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL, 2016, 68, 560–567. https://doi.org/10.1080/01635581.2016.1156713
Elucidating the interplay between the DNA Damage Response and Repair (DDR/R) network and the immune system in cancer and autoimmunity (V.L. Souliotis)
The deregulated interplay between the DDR/R network and the immune system plays a crucial role in the pathogenesis and progression of cancer and systemic autoimmune diseases. Thus, unraveling the molecular mechanisms of this interplay can be exploited for understanding pathogenesis and progression of these diseases, as well as to discover new treatment opportunities in the field.
In this project, using established cell lines and primary biological samples from cancer patients (multiple myeloma, head and neck cancer, lung cancer) and autoimmune diseases (lupus erythematosus, Rheumatoid arthritis, systemic sclerosis, Behçet's disease) at different stages of the disease, we test the hypothesis that the deregulated interplay between the DDR/R network and the immune system provides a putative pathogenetic mechanism in cancer and autoimmunity.
Souliotis, V.L., Vlachogiannis, N.I., Pappa, M., Argyriou, A., Ntouros, P.A., Sfikakis, P.P., DNA Damage Response and Oxidative Stress in Systemic Autoimmunity. International journal of molecular sciences, 2019, 21, E55. https://doi.org/10.3390/ijms21010055
Souliotis, V.L., Vlachogiannis, N.I., Pappa, M., Argyriou, A., Sfikakis, P.P., DNA damage accumulation, defective chromatin organization and deficient DNA repair capacity in patients with rheumatoid arthritis. Clinical Immunology, 2019, 203, 28–36. https://doi.org/10.1016/j.clim.2019.03.009
Souliotis, V.L., Vougas, K., Gorgoulis, V.G., Sfikakis, P.P., Defective DNA repair and chromatin organization in patients with quiescent systemic lupus erythematosus. Arthritis research & therapy, 2016, 18, 182. https://doi.org/10.1186/s13075-016-1081-3
Gkotzamanidou, M., Terpos, E., Bamia, C., Kyrtopoulos, S.A., Sfikakis, P.P., Dimopoulos, M.A., Souliotis, V.L., Progressive changes in chromatin structure and DNA damage response signals in bone marrow and peripheral blood during myelomagenesis. Leukemia, 2014, 28, 1113–1121. https://doi.org/10.1038/leu.2013.284
Evaluation of bioactive compounds (P. Georgiadis, V. Pletsa)
The development of bioactive compounds against selected therapeutic targets and their evaluation in relevant preclinical disease models/intervention studies, in the context of drug design and discovery, is of utmost importance for chemoprevention and treatment.
The Comet Assay has been widely used for detecting primary DNA damage in individual cells. The micronucleus (MN) test is also a well-established assay for detecting clastogenicity and aneugenicity. We utilize these two assays in order to assess the genotoxicity or anti-genotoxicity of novel bioactive synthetic or natural compounds or mixtures.
On the other hand, chemotherapeutic agents inducing DNA damage may activate cell death by apoptosis or necrosis.The molecular basis underlying the decision- making process is currently the subject of intense investigation because a deeper understanding of how a given chemotherapy affects all of the signaling pathways involved in cell death is highly relevant in order to develop more effective therapeutics and prevent recurrence. We assess geno/cytotoxicity of novel bioactive lead compounds and further study the molecular mechanism underlying their action in view of their use as chemotherapeutic drugs.We emphasize on the identification/validation of new prognostic chemo-sensitivity/resistance biomarkers, related to cell death pathways and the cell’s response to DNA damaging insults.
Papadodima, O., Moulos, P., Koryllou, A., Piroti, G., Kolisis, F., Chatziioannou, A., Pletsa, V., Modulation of pathways underlying distinct cell death mechanisms in two human lung cancer cell lines in response to S<inf>N</inf>1 methylating agents treatment. PLoS ONE, 2016, 11. https://doi.org/10.1371/journal.pone.0160248
The DNA damage response and repair (DDR/R) network as a therapeutic target
The mechanistic basis for the link between DNA repair efficiency and the response to anti-myeloma therapy.
We study epigenetic modifications, changes in the gene expression profiles, oxidative stress, abasic sites and DDR/R alterations in established cell lines and primary cells from cancer patients with different response rates using advanced genome-wide methodologies in combination with biochemical and new imaging technology based on confocal microscopy. The study of these alterations holds great promise for contributing to the outcome of therapy on an individual basis, thus providing unique tools for the discovery of biomarkers and therapeutic targets.
Gkotzamanidou, M., Terpos, E., Bamia, C., Munshi, N.C., Dimopoulos, M.A., Souliotis, V.L., DNA repair of myeloma plasma cells correlates with clinical outcome: The effect of the nonhomologous end-joining inhibitor SCR7. Blood, 2016, 128, 1214–1225. https://doi.org/10.1182/blood-2016-01-691618
Stefanou, D.T., Bamias, A., Episkopou, H., Kyrtopoulos, S.A., Likka, M., Kalampokas, T., Photiou, S., Gavalas, N., Sfikakis, P.P., Dimopoulos, M.A., Souliotis, V.L., Aberrant dna damage response pathways may predict the outcome of platinum chemotherapy in ovarian cancer. PLoS ONE, 2015, 10, e0117654. https://doi.org/10.1371/journal.pone.0117654
Gkotzamanidou, M., Sfikakis, P.P., Kyrtopoulos, S.A., Bamia, C., Dimopoulos, M.A., Souliotis, V.L., Chromatin structure, transcriptional activity and DNA repair efficiency affect the outcome of chemotherapy in multiple myeloma. British journal of cancer, 2014, 111, 1293–1304. https://doi.org/10.1038/bjc.2014.410
In-house capabilities coupled with strategic networks and partnerships
Targeted delivery of chemotherapeutics through nanocarriers (V. Pletsa)
Nanocarriers as drug delivery systems are becoming very important due to their potential to incorporate a wide range of molecules, improve bioavailability and allow controlled release of the encapsulated drugs. In collaboration with the Program of Biomimetics & Nanobiotechnology, we evaluate, in vitro, ex vivoand in vivo, the biological action of nano-dispersions as carriers of lipophilic lead compounds in relevant target tissues.
Theochari, I., Papadimitriou, V., Papahatjis, D., Assimomytis, N., Pappou, E., Pratsinis, H., Xenakis, A., Pletsa, V., Oil-In-Water Microemulsions as Hosts for Benzothiophene-Based Cytotoxic Compounds: An Effective Combination. BIOMIMETICS, 2018, 3. https://doi.org/10.3390/biomimetics3020013
Combination treatment of BRAF-V600E inhibitors and genotoxic drugs in colorectal cancer (V.L. Souliotis)
Combination therapy, a treatment modality that potentially reduces drug efficacy and resistance through combining two or more therapeutic agents, is a cornerstone of cancer therapy. In this project, we study the hypothesis that combination treatment using BRAF/V600E inhibitors and genotoxic drugs, may decrease cancer resistance and recurrence.
Epigenetics & DNA methylation-based biomarkers (P. Georgiadis)
The rise of interest in epigenetic mechanisms has allowed the identification of a new type of biomarker, DNA methylation, which is of great potential for many applications. In some cases, DNA methylation based biomarkers have proven to be more specific and sensitive than commonly used protein biomarkers, which could clearly justify their use in clinical practice and research. Weutilize genome-wide screening methods (Illumina InfiniummethylationEPICbeadchip) and locus- or gene-specific analysis (pyrosequencing) in different types of samples such as tissues and FFPE samples, as well as liquid biopsies.
Hatzioannou, A., Banos, A., Sakelaropoulos, T., Fedonidis, C., Vidali, M.-S., Kohne, M., Handler, K., Boon, L., Henriques, A., Koliaraki, V., Georgiadis, P., Zoidakis, J., Termentzi, A., Beyer, M., Chavakis, T., Boumpas, D., Tsirigos, A., Verginis, P., An intrinsic role of IL-33 in Treg cell-mediated tumor immunoevasion. Nature immunology, 2020, 21, 75–85. https://doi.org/10.1038/s41590-019-0555-2
EnviroGenomarkers: Genomics biomarkers of environmental health, EU FP7 Collaborative project(co-ordinated by S.A Kyrtopoulos), duration: 2009-2013,
Exposomics: Enhanced exposure assessment and -omic profiling for high priority environmental exposures in Europe, EU FP7 Collaborative project (co-ordinated by Prof. P. Vineis, Imperial College School of Public Health); duration:
PHYTOME-Phytochemicals to reduce nitrite in meat products, EU FP7 SME (co-ordinated by Prof T. M. De Kok, Maastricht university): duration:2013-2016;
STHENOS: Targeted Therapeutic approaches against degenerative Diseases, with emphasis on cancer and aging: within the frame of KRIPIS (ESPA 2014-2020) Developmental proposals from research institutions. Duration:2013-2015.
STHENOS β: “Targeted therapeutic approaches against degenerative diseases with special focus on cancer and ageing-optimisation of the targeted bioactive molecules” within the frame of KRIPIS ΙΙ(ESPA 2014-2020) (MIS 5002398), Duration:2017-2020.
FunGlucan: Development of a novel functional food enriched with β-glucan isolated from edible mushrooms from Greek habitats (EREVNO-KAINOTOMO-DIMIOYRGO-ΕSPA 2014-2020). (co-ordinated by Assoc. Prof A. Kyriacou, Harokopio university);Duration:2018-2021
Collaborations with universities and academic institutes
Laboratory of General and Agricultural Microbiology, Department of Crop Science, Agricultural Universityof Athens
Department of Nutrition and Dietetics, Harokopio University
Department of Clinical Therapeutics, National and Kapodistrian University of Athens Medical School
First Department of Propaedeutic Internal Medicine and Joint Rheumatology Program, National and Kapodistrian University of Athens Medical School,
Department of Physiology, National and Kapodistrian University of Athens Medical School
Section of Botany, Faculty of Biology, School of Science, National and Kapodistrian University of Athens
Centre of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens
Department of Biochemistry and Biotechnology, School of Health Sciences, University of Thessaly
School of Medicine, University of Crete
Nutrition-Gut-Brain Interactions Research Centre (NGBI), Orebro University, Sweden
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
Education & Training
The members of the team participate in the administration/organization and teaching in the interdepartmental, interdisciplinarypostgraduate programmes “Oncology: from Oncogenesis to Therapy”, (Joint Master’s Degree, University of Crete/National Hellenic Research Foundation) and “Bioenterpreneurship” http://bioepixirin.bio.uth.gr/, (joint Master’s Degree, University of Thessaly/National Hellenic Research Foundation.
Science & Society
The members of the team actively and regularly participate in
the organization of the “Science & Society” annual event of the National Hellenic Research Foundation aiming at communicating front line scientific issues to the general public: "Translational research: the coalescence of Biology and Medicine for the effective treatment of multifactorial diseases”, March 2015 / "Safe and health promoting food, truths and lies”, March 2016 / "Diet in the Mediterranean: Historical Aspects and Biochemical Approaches", March 2017 / "Youth, Antiaging and Longevity: Modern Approaches to Biological Age through the Historical and Biological Sciences", March 2018
the Researcher’s Night and Athens Science Festival events