Transcriptomic analysis of rare and ultra-rare sarcomas: toward a better understanding of these challenging cancers

Small round cell sarcomas are rare, aggressive tumours that arise in soft tissue or bone. They include Ewing sarcoma (EWS) and ultra-rare entities such as CIC-rearranged (CDS) and BCOR-rearranged (BCS) sarcomas, recognised as distinct diseases in the 2020 classification by the World Health Organization. Despite this, they are often treated with Ewing-type chemotherapy. CDS usually show poorer response and greater aggressiveness, whereas BCS tend to respond better, with outcomes similar to EWS. Dedicated studies are crucial to understand their molecular drivers. The project aims to comprehensively profile the transcriptome, identify key molecular pathways and potential biomarkers and facilitate the development of innovative therapeutic strategies. Ultimately, the goal is to improve our understanding of the biology of these tumours, particularly CDS tumours, which have the poorest response to chemotherapy and the worst prognosis. We performed bulk RNA sequencing on EWS, CDS and BCS tumour samples, and single-cell RNA sequencing on CDS and EWS patient-derived xenograft lines, as well as EWS cell lines. Bulk RNA-seq analysis revealed enrichment of genes involved in endothelial differentiation in CDS. Ectopic expression of these genes by cancer cells suggests possible activation of vasculogenic mimicry, which may underlie the aggressive and invasive behavior of CDS.