Epigenome-based precision medicine
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
In an effort to better understand the molecular basis of this enigmatic tumor, we have performed comprehensive epigenome profiling in cell lines, and we have shown that Ewing sarcoma is an ‘enhancer disease’, characterized by widespread deregulation of enhancers downstream of the EWS-FLI1 fusion oncogene (the only genetic aberration consistently observed in Ewing sarcoma tumors). Enhancers are cell type specific and dynamically utilized regulatory elements that control the temporal and spatial activation of gene expression. They can contribute to cancer formation in a variety of ways. We have reported that EWS-FLI1 drives widespread reprogramming of enhancers by introducing de novo enhancer elements (Ewing-specific enhancers) and by repressing enhancers that are active in many tissues and cell types. This enhancer signature is highly specific and functionally linked to oncogenic transformation by EWS-FLI1.
We have confirmed the clinical relevance of our finding in a large cohort of Ewing sarcoma patients. More specifically, we dissected epigenetic heterogeneity at three hierarchical levels: among cancer types, between patients (inter-individual heterogeneity), and within tumors (intra-tumor heterogeneity). We identified a unique and predictive epigenomic enhancer signature that distinguishes Ewing sarcoma from other cancers, but also observed widespread epigenetic heterogeneity. Intriguingly, inter-patient epigenetic differences gave rise to a continuous epigenetic disease spectrum underlying Ewing sarcoma, rather than to disease subtypes as observed for other cancers. This spectrum has two biologically interpretable dimensions: degree of Ewing-ness and mesenchymal vs. stem-like signature.
Ongoing Work – Translating basic research into more precise therapies
Based on the novel concept that Ewing sarcoma is an ‘enhancer-disease’ and using state-of-the-art technologies that combine wet-lab and computational methods, 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 to overcome resistance to therapy
- Decipher intra-tumor epigenetic heterogeneity to understand tumor evolution and overcome resistance to therapy
Lawson JT, Tomazou EM, Bock C, Sheffield NC. MIRA: An R package for DNA methylation-based inference of regulatory activity. Bioinformatics. 2018 Mar 1. doi: 10.1093/bioinformatics/bty083. [Epub ahead of print]
Sheffield NC, Pierron G, Klughammer J, Datlinger P, Schönegger A, Schuster M, Hadler J, Guillemot D, Lapouble E, Freneaux P, Champigneulle J, Bouvier R, Walder D, Ambros IM, Hutter C, Sorz E, Amaral AT, Álava Ed, Schallmoser K, Strunk D, Rinner B, Liegl-Atzwanger B, Huppertz B, Leithner A, Pinieux Gd, Terrier P, Laurence V, Michon J, Ladenstein R, Holter W, Windhager R, 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.
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