Eleni Tomazou Group
Background – Ewing sarcoma is an unmet medical need
Ewing sarcoma is a bone and soft tissue cancer of children and young adults. It is one of the cancers with fewest genetic lesions. Despite its simple and homogeneous genome, Ewing sarcoma is among the pediatric tumors with the lowest survival rates. The limited understanding of the biological mechanisms that underlie tumor initiation and progression in combination with the lack of molecular patient stratification has hampered the development of novel therapies. Furthermore, the low rate of somatic mutations in Ewing sarcoma provides little scope for genetically targeted drugs. Consequently, treatment protocols for Ewing sarcoma have changed little in the last 25 years, relying mainly on cytotoxic chemotherapy, radiotherapy and/or surgery, and patient survival has not substantially improved.
Recent research - Novel concepts in Ewing sarcoma biology
Our main research goal is to uncover the roles of epigenetic deregulation as an oncogenic mechanism, with a focus on fusion-driven pediatric sarcomas. Epigenetic mechanisms lead to changes in gene function that are not based on changes in the DNA sequence but are passed on to daughter cells. We were among the first to investigate the epigenome of Ewing sarcoma, showing that this cancer is characterized by widespread reprogramming of gene regulatory elements. Moreover, we performed the first large-scale analysis of epigenetic heterogeneity in Ewing sarcoma tumors, revealing an unexpected association of the corresponding epigenetic signatures with metastatic status at diagnosis. In a proof-of-concept study exploiting the unique epigenetic signatures of pediatric tumors towards precision medicine, we have developed a minimally invasive assay for tumor detection and classification as well as for monitoring therapy induced toxicity.
Ongoing Work – Translating basic research into more precise therapies
Our approach towards precision medicine for pediatric sarcomas is based on a concept that goes beyond the genome. Using state-of-the-art technologies that combine wet-lab and computational methods, patient material (tumor tissues and liquid biopsies) as well as 3D in vitro models we aim to:
- Identify, validate and target actionable enhancers to provide proof-of-concept for enhancer therapy
- Infer developmental stage(s) of cell of origin using the Ewing sarcoma disease spectrum defined by inter-patient heterogeneity at enhancer elements
- Decipher intra-tumor epigenetic heterogeneity to understand tumor evolution
- Elucidate non-genetic mechanisms of therapy resistance to reveal novel therapeutic strategies
- Develop and clinically validate minimally invasive biomarkers for disease monitoring during therapy
Projects and Funding
Characterizing and targeting the Ewing sarcoma microenvironment to overcome resistance to therapy
FWF TAI 592
Cracking the ribosome code of drug resistance in sarcomas
FWF P 34958
Interplay of fusion genes and cellular context in sarcoma
Validation of a liquid biopsy based molecular diagnostic toolkit for pediatric sarcomas
- Epigenome profiling in Ewing sarcoma cell lines (https://medical-epigenomics.org/papers/tomazou2015/)
- Genome wide DNA methylation profiling in 140 Ewing sarcoma tumors (https://www.medical-epigenomics.org/papers/sheffield2017/)
- Whole genome sequencing (10x coverage) data of cell free DNA from 126 patients with pediatric sarcomas (http://ews-liquid-biopsy.computational-epigenetics.org/)
LIQUORICE: Detection of epigenetic signatures in liquid biopsies based on whole-genome sequencing data (http://liquorice.computational-epigenetics.org)
- Peneder P*, Stütz AM*, Surdez D, Krumbholz M, (25 additional co-authors), Boye K, Ambros PF, Delattre O, Metzler M, Bock C, Tomazou EM#. Multimodal analysis of cell-free DNA whole genome sequencing for pediatric cancers with low mutational burden. Nature Communications. 2021. 12(3230) doi: 10.1038/s41467-021-23445-w.
- Terlecki-Zaniewicz S, Humer S, Eder T, Schmoellerl J, Heyes E, Manhart G, Kuchynka N, Parapatics K, Liberante F, Müller A, Tomazou EM, Grebien F. Biomolecular Condensation of NUP98-Fusion Proteins Drives Leukemogenic Gene Expression. Nature Structural & Molecular Biology. 2021. 28(2):190-201. doi: 10.1038/s41594-020-00550-w.
- Grünewald TGP, Cidre-Aranaz F, Surdez D, Tomazou EM, de Álava E, Kovar H, Sorensen PH, Delattre O, Dirksen U. Ewing sarcoma. Nat Rev Dis Primers. 2018 Jul 5;4(1):5. doi: 10.1038/s41572-018-0003-x.
- Sheffield NC, Pierron G, Klughammer J, Datlinger P, (30 additional co-authors), Dirksen U, Ambros PF, Delattre O, Kovar H, Bock C#, Tomazou EM#. DNA methylation heterogeneity defines a disease spectrum in Ewing sarcoma. Nature Medicine. 2017 Mar;23(3):386-395. doi: 10.1038/nm.4273
- Tomazou EM*, Sheffield NC*, Schmidl C, Schuster M, Schönegger A, Datlinger P, Kubicek S, Bock C, and Kovar H. Epigenome mapping reveals distinct modes of gene regulation and widespread enhancer reprogramming by the oncogenic fusion protein EWS-FLI1. Cell Reports. 2015 Feb 24;10(7):1082-95. doi: 10.1016/j.celrep.2015.01.042
About Eleni Tomazou
Eleni Tomazou has been a principal investigator at the St. Anna Children’s Cancer Research Institute (CCRI, Vienna, Austria) since January 2018. She has established a research program focusing on epigenome-based precision medicine at CCRI. She has a strong background in epigenomics research and two years’ experience in clinical diagnostics and management of a high-throughput diagnostics lab. Prior to joining CCRI, she did her PhD at the Wellcome Trust Sanger Institute (Cambridge, UK) and postdoctoral training at the Broad Institute and the Harvard Department for Stem Cell and Regenerative Biology (Cambridge, USA). She is a 2016 recipient of the Elise Richter Fellowship, a prestigious career development grant for female scientists offered by the Austrian Science Foundation (FWF).