Molecular Biology of Solid Tumours
The Molecular Biology Group focuses predominantly on basic research with the aim of translating clinical observations into molecular patterns, and molecular patterns into diagnostic/prognostic tools and novel treatment options. For many years, our research has focused on Ewing sarcoma. There is an urgent need for new treatment options for this very malignant form of bone cancer in children and adolescents. Due to its relatively simple genetic makeup, this disease is particularly open to further research.
The search for the right medication.
The central genetic aberration of Ewing sarcoma is a fusion between the Ewing sarcoma gene EWS and the ETS oncogene FLI1 that results in the production of an aberrant gene regulatory protein, EWS-FLI1. Thus, the study of Ewing sarcoma also serves as a seminal example for ETS oncogene-driven oncogenesis in human cancer. The overall aim of our research is to identify druggable vulnerabilities in the molecular pathways that drive Ewing sarcoma pathogenesis. Since transcription factors - such as EWS-FLI1 – have thus far represented rather inaccessible therapeutic targets, we want to decode the molecules and biochemical pathways, which are active up- and downstream of EWS-FLI1 and are modulating EWS-FLI1 expression and its effects. We are approaching this goal through a multidisciplinary systems approach (European Framework 7 program funded project “ASSET”) using experimental perturbation in Ewing sarcoma cell lines, in-silico prediction and validation in primary tumour samples.
Studies of gene regulatory networks of the protein EWS-FLI1.
Our research focusses on the gene regulatory networks of EWS-FLI1. We use pangenomic screening approaches (mRNA, microRNA, transcription factor binding and epigenetic profiling by array technologies and high-throughput sequencing) to generate hypotheses about mechanisms of altered gene regulation in Ewing sarcoma. These are subsequently tested by targeted pathway perturbations using genetic (RNA interference, ectopic overexpression and targeted mutagenesis of genes of interest) and chemical (small molecule inhibitors) tools. We also investigate the influence of the microenvironment (e.g. hypoxia, immune cells) on the EWS-FLI1 gene regulatory network in vitro, and study characteristics associated with malignancy and metastasis formation in European (ERA-NET project PROVABES; FP7 project ASSET) and internationally funded (Liddy Shriver Sarcoma initiative) collaborative projects. Finally, we engage in Europe-wide clinical Ewing sarcoma trials (Euro Ewing 99, Ewing 2008; European Ewing Sarcoma Consortium) to prospectively test the potential prognostic utility of EWS-FLI1 and its downstream effectors in terms of the course of the disease and according treatments .
Katschnig AM, Kauer MO, Schwentner R, Tomazou EM, Mutz CN, Linder M, Sibilia M, Alonso J, Aryee DNT, Kovar H. (2017) EWS-FLI1 perturbs MRTFB/YAP-1/TEAD target gene regulation inhibiting cytoskeletal autoregulatory feedback in Ewing sarcoma. Oncogene. 2017 Jul 3. doi: 10.1038/onc.2017.202. [Epub ahead of print].
Sheffield NC, Pierron G, Klughammer J, Datlinger P, Schönegger A, Schuster M, Hadler J, Surdez D, Guillemot D, Lapouble E, Freneaux P, Champigneulle J, Bouvier R, Walder D, Ambros IM, Hutter C, Sorz E, Amaral AT, de Álava E, Schallmoser K, Strunk D, Rinner B, Liegl-Atzwanger B, Huppertz B, Leithner A, de Pinieux G, Terrier P, Laurence V, Michon J, Ladenstein R, Holter W, Windhager R, Dirksen U, Ambros PF, Delattre O*, Kovar H*, Bock C*, Tomazou EM* (2017) DNA methylation heterogeneity in Ewing sarcoma defines an epigenetic disease spectrum underlying a genetically homogeneous developmental cancer. Nature Med., 23:386-395.
Schwentner R, Papamarkou T, Kauer MO, Stathopoulos V, Yang F, Bilke S, Meltzer PS, Girolami M, Kovar H. (2015) EWS-FLI1 employs an E2F switch to drive target gene expression. Nucleic Acids Res. 43(5):2780-9 Tomazou EM, Sheffield NC, Schmidl C, Schuster M, Schönegger A, Datlinger P, Kubicek S, Bock C, Kovar H (2015) Epigenome mapping reveals distinct modes of gene regulation and widespread enhancer reprogramming by the oncogenic fusion protein EWS-FLI1. Cell Reports, 10:1-14.
Ban J, Aryee DN, Fourtouna A, van der Ent W, Kauer M, Niedan S, Machado I, Rodriguez-Galindo C, Tirado OM, Schwentner R, Picci P, Flanagan AM, Berg V, Strauss SJ, Scotlandi K, Lawlor ER, Snaar-Jagalska E, Llombart-Bosch A, Kovar H. (2014) Suppression of deacetylase SIRT1 mediates tumor-suppressive NOTCH response and offers a novel treatment option in metastatic Ewing sarcoma. Cancer Res. 15,74:6578-88.