A Practical Compass to Biological Digital Resources and Omics Integration in Ewing Sarcoma.

Ewing sarcoma (EwS) is a paradigmatic fusion-driven cancer in which oncogenic FET::ETS transcription factor fusions orchestrate complex regulatory, epigenomic, transcriptional, and proteomic programs. Despite extensive molecular profiling, biological insight, and translational progress, EwS are strongly shaped by how data are generated, structured, and shared across heterogeneous initiatives. Fragmented cohorts, uneven molecular depth, and limited longitudinal sampling influence both integrative analyses and systems-level interpretation. This chapter is organized around this structural reality. It first maps the current EwS data landscape, including patient-derived and preclinical omics datasets, profiling initiatives, repositories, and annotation resources, highlighting how their design and governance define the biological questions that can be addressed. It then synthesizes key biological insights derived from genomic, transcriptomic, epigenomic, proteomic, and single-cell studies, with an emphasis on regulatory logic, transcriptional plasticity, and context-dependent vulnerabilities revealed through integrative analyses. Particular attention is given to the predominance of preclinical approaches in systems-level EwS biology, reflecting the experimental resolution required to interrogate regulatory mechanisms that remain largely inaccessible in most patient cohorts. Finally, the chapter examines how these observations motivate a shift from opportunistic data aggregation toward intentionally designed EwS-specific data ecosystems. It discusses the technical, ethical, and organizational requirements for longitudinal, multilayer profiling and federated data access, and argues that such infrastructures are necessary to support reproducible systems biology and therapeutic translation in EwS.