Epigenetic mechanisms include DNA methylation, histone modification/remodeling and the action of non-coding RNAs, which are intertwined processes essential for the inheritance of gene expression patterns that determine development, cellular identity or differentiation. Deregulation of the epigenetic machinery has been implicated in various pathological conditions including cancer, which has important implications for biomarker development and therapy using epigenetic drugs.
We employed genome-scale epigenomic analyses to define targets of differential DNA methylation, chromatin modification or miRNA expression in different primary tumors and tumor cell lines to define epigenetic biomarkers and to discover epigenetic drivers of tumorigenesis (Saito, Egger et al., 2006; Gal-Yam, Egger et al, 2008; Hassler et al, 2016; Exner et al, 2015). Using xenograft models, we demonstrated the efficacy of DNMT inhibitors towards T- cell lymphoma (Hassler et al, 2012).
Our main goal is to understand the causative function of key epigenetic proteins such as DNA methyltransferases or histone deacetylases for tumorigenesis. We want to identify the specific targets of these enzymes, in order to better understand the biological impact for diverse cancers. Furthermore, we aim to translate our findings into clinical settings to develop epigenetic biomarkers with potential use for diagnostic, prognostic or predictive purposes in liquid biopsies.
We use different preclinical models including tumor organoids and transgenic mouse models but also primary tumor specimen as our model systems. Molecular tools include genome-wide chromatin (ATAC-Seq, ChIP-Seq) and DNA methylation analyses (RRBS, Illumina arrays), as well as proteomics (phospho, acetylomics).
Epigenetics of ALK driven cancers
The ALK tyrosine kinase acts as an oncogene in diverse cancers including anaplastic large cell lymphoma (ALCL), neuroblastoma or non-small cell lung cancer (NSCLC). We aim to understand the epigenetic pathways implicated in lymphomagenesis and NSCLC employing transgenic mouse models and primary patient profiling, respectively. In particular we focus on the role of the DNA methyltransferase DNMT1 and the histone deacetylases HDAC1/2 in ALK driven lymphoma. In NSCLC, we study genome-wide DNA methylation and miRNA expression in primary patient samples to identify key ALK dependent epigenetic alterations.
Identification of epigenetic biomarkers in colorectal and prostate cancer
Using DNA methylation profiling and data mining of public databases we aim to develop suitable epigenetic biomarkers for diagnostic, prognostic or predictive purposes. We aim to develop these markers as liquid biopsy markers for plasma testing of cancer patients. This project is mainly pursued by group members within the LBI Applied Diagnostics (https://lbiad.lbg.ac.at/).
Generation of tumor organoids
The development of 3D tumor cell cultures from primary patient material is the basis for future precision medicine, since it retains the in vivo attributes of a given tumor including its heterogeneity and mutation status. In this project, we develop tumor organoids primary patient specimen including colon, prostate and lung. We aim to generate a living biobank as research tools and for large scale drug testing. This project is also mainly pursued by group members within the LBI Applied Diagnostics (https://lbiad.lbg.ac.at/).
- Hassler, M. R. et al., 2016. Insights into the Pathogenesis of Anaplastic Large-Cell Lymphoma through Genome-wide DNA Methylation Profiling. Cell Reports 17, 596-608, dx.doi.org/10.1016/j.celrep.2016.09.018
- Exner, R. et al., 2015. Potential of DNA methylation in rectal cancer as diagnostic and prognostic biomarkers. British Journal of Cancer, 113(7), pp.1035-1045, dx.doi.org/10.1038/bjc.2015.303
- Gal-Yam, E. N. et al., 2008. 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, dx.doi.org/10.1073/pnas.0806437105
- Saito, Y. et al., 2006. 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, dx.doi.org/10.1016/j.ccr.2006.04.020
- Egger, G. et al., 2006. 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, http://dx.doi.org/10.1073/pnas.0604602103
The Egger group is funded by FWF:
Project 1: “Dissecting the role of HDAC1 in T-cell lymphoma” (I 4066, 2019-2021)
Project 2: “Plasticity of ontogeny of energy saving mechanisms in heterothermic mammals” (P 31577, 2018-2022, Co- PI)
And is part of the FWF-funded Doc funds program “International PhD Program in Translational Oncology" (IPPTO).
The Egger group is part of the Ludwig Boltzmann Institute Applied Diagnostics funded by the Ludwig Boltzmann Gesellschaft and Academic and Industrial Partners:
The Egger group was funded by the OeNB:
Project 1: “Epigenetic profiling of premalignant and malignant stages of cholangiocarcinoma (2013-2017)
Project 2: “The role of epigenetic biomarkers for prostate cancer before and after hormone ablation therapy (2008-2012)
The Egger group was funded by the Herzfelder’sche Familienstiftung:
Project: “Identification of novel nuclear targets of the oncogenic tyrosine kinase NPM-ALK” (2015-2019)
The Egger group was part of the Innovative training network “ALKATRAS - ALK Activation as a target of TRAanslational Science: Break free from cancer” funded by the EU, H2020-MSCA-ITN (2015-2019)
The Egger group was funded by the FWF:
Project: “The function of DNMT1 for NPM-ALK driven lymphomagenesis” (P 27616, 2014-2018)
The Egger group was funded by the FFG:
Project: “FFG-Talents, Internships for Students (2018, 2019)