Medical University of Vienna
Department of Pathology
Währinger Gürtel 18-20
1090 Vienna, Austria
Phone: +43 1 40160-22390
Fax: +43 1 40160-51930
My research interest lies in the field of medical epigenomics and cancer. Using different preclinical models, we are aiming to understand the causality of epigenetic aberrations in cancer, how epigenetic signatures are generated and how they can be reversed and remodeled. We have employed genome-scale analyses to define targets of differential DNA methylation in primary tumors to define epigenetic biomarkers and to discover epigenetic drivers of tumorigenesis. Furthermore, as a main objective of the recently established Ludwig Boltzmann Institute Applied Diagnostics we have developed different organotypic 3D tissue culture models from primary patient material and genetic mouse models, which we use to perform functional molecular analyses and drug testing.
Epigenetic regulation of tumor cell plasticity and therapy resistance in colorectal cancer. We have shown that aberrant epigenetic modifications (i.e. DNA methylation) have diagnostic and prognostic value in CRC1. Changes in chromatin accessibility and DNA methylation have been identified in EMT-related genes including CDH1, which has been correlated to tumor invasiveness and migration in different cancer entities2. Our lab has recently established patient-derived 3D organoid cell culture systems from normal colon epithelia and colorectal cancer. Since these models provide a more physiological in vitro system as compared to established cell lines, we hypothesize that they will offer an in-depth insight into the relation of epigenetic mechanisms, EMT and drug resistance. We aim to establish organoid based EMT models by overexpression of EMT-TFs (SNAI1, ZEB1, TWIST1) or by treatment with EMT-inducing cytokines (TGF-ß,TNF-a)3. Furthermore, we will establish the functional aspects of epigenetics for drug resistance mechanisms by generating drug-resistant organoids after low-dose chemotherapy (with GS). Using genome-wide DNA methylation analyses (RRBS) and chromatin accessibility assays (ATAC-Seq with PM) we will map epigenetic changes associated with the induction of EMT and drug resistance. The relevance of the identified common pathways will be functionally evaluated using CRISPR/Cas9-based genome editing. Epigenetic drugs (including DNMT and HDAC inhibitors) will be used to test their ability to re-sensitize resistant organoids and to reverse EMT.
- Exner, R.; Pulverer, W.; Diem, M.; Spaller, L.; Woltering, L.; Schreiber, M.; Wolf, B.; Sonntagbauer, M.; Schröder, F.; Stift, J.; et al. Potential of DNA Methylation in Rectal Cancer as Diagnostic and Prognostic Biomarkers. Br. J. Cancer 2015, 113 (7), 1035–1045. doi.org/10.1038/bjc.2015.303.
- Skrypek, N.; Goossens, S.; De Smedt, E.; Vandamme, N.; Berx, G. Epithelial-to-Mesenchymal Transition: Epigenetic Reprogramming Driving Cellular Plasticity. Trends Genet. 2017, 33 (12), 943–959. doi.org/10.1016/j.tig.2017.08.004.
- Hahn, S.; Nam, M.-O.; Noh, J. H.; Lee, D. H.; Han, H. W.; Kim, D. H.; Hahm, K. B.; Hong, S. P.; Yoo, J.-H.; Yoo, J. Organoid-Based Epithelial to Mesenchymal Transition (OEMT) Model: From an Intestinal Fibrosis Perspective. Sci. Rep. 2017, 7 (1), 2435. doi.org/10.1038/s41598-017-02190-5.
- Hassler, M. R., Pulverer, W., Lakshminarasimhan, R., Redl, E., Hacker, J., Garland, G. D., Merkel, O., Schiefer, A. I., Simonitsch-Klupp, I., Kenner, L., Weisenberger, D. J., Weinhaeusel, A., Turner, S. D. & Egger, G. Insights into the Pathogenesis of Anaplastic Large-Cell Lymphoma through Genome-wide DNA Methylation Profiling. Cell Rep 17, 596-608, doi:10.1016/j.celrep.2016.09.018 (2016).
- Exner, R., Pulverer, W., Diem, M., Spaller, L., Woltering, L., Schreiber, M., Wolf, B., Sonntagbauer, M., Schroder, F., Stift, J., Wrba, F., Bergmann, M., Weinhausel, A. & Egger, G. Potential of DNA methylation in rectal cancer as diagnostic and prognostic biomarkers. Br J Cancer 113, 1035-1045, doi:10.1038/bjc.2015.303 (2015)
- Hassler, M. R., Klisaroska, A., Kollmann, K., Steiner, I., Bilban, M., Schiefer, A. I., Sexl, V. & Egger, G. Antineoplastic activity of the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine in anaplastic large cell lymphoma. Biochimie 94, 2297-2307, doi:10.1016/j.biochi.2012.05.029 (2012).
- Gal-Yam, E. N*., Egger, G.*, Iniguez, L., Holster, H., Einarsson, S., Zhang, X., Lin, J. C., Liang, G., Jones, P. A. & Tanay, A. Frequent switching of Polycomb repressive marks and DNA hypermethylation in the PC3 prostate cancer cell line. Proc Natl Acad Sci U S A 105, 12979-12984, doi:10.1073/pnas.0806437105 (2008). (*Co-first author).
- Egger, G., Aparicio, A. M., Escobar, S. G. & Jones, P. A. Inhibition of histone deacetylation does not block resilencing of p16 after 5-aza-2'-deoxycytidine treatment. Cancer Res 67, 346-353, doi:10.1158/0008-5472.CAN-06-2845 (2007)
- Egger, G., Jeong, S., Escobar, S. G., Cortez, C. C., Li, T. W., Saito, Y., Yoo, C. B., Jones, P. A. & Liang, G. Identification of DNMT1 (DNA methyltransferase 1) hypomorphs in somatic knockouts suggests an essential role for DNMT1 in cell survival. Proc Natl Acad Sci U S A 103, 14080-14085, doi:10.1073/pnas.0604602103 (2006).
- Saito, Y., Liang, G*., Egger, G.*, Friedman, J. M., Chuang, J. C., Coetzee, G. A. & Jones, P. A. Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells. Cancer Cell 9, 435-443, doi:10.1016/j.ccr.2006.04.020 (2006).(*equal contribution)