GIGA 2021 Annual Report 31 Ewing sarcoma is a bone and soft tissue cancer that predominantly affects children and young adults. Current treatments are limited to intensive chemotherapy that can be brutal and have multiple short-term and long-term side effects. Ewing sarcomas are typified by a chromosomal translocation (i.e. an exchange of DNA regions between two chromosomes) leading to a fusion between two genes: EWS and FLI1. The resulting EWS-FLI1 chimeric protein carries a DNA-binding region from FLI1 that brings the potent gene-activating region of EWS to inappropriate regions of the genome. According to the current model, the consequence of the presence of EWS-FLI1 is a complete deregulation of the gene expression landscape in Ewing sarcoma cells contributing to tumor growth and disease progression. To date, deregulation of gene expression has been exclusively studied at the quantitative level, with hundreds of mRNAs, the key intermediate in the process of gene expression being up or down-regulated by EWS-FLI1, leading to abnormal production of the corresponding proteins and deregulated cellular functions. In a collaborative study with Institut Curie in Paris, the Laboratory of Gene expression and Cancers (GIGA-MBD) took a new look at how EWSFLI1 might modify the gene expression landscape in Ewing sarcoma cells. The researchers hypothesized that EWS-FLI1 might also perturb gene expression programs at the qualitative levels, by affecting mRNA splicing. Splicing of mRNA is a fundamental step in gene expression that allows the cells to express multiple variants (they are called isoforms) of proteins, from a single gene. In their study, the collaborative French and Belgian teams have shown that beyond their role in transcription, EWS-FLI1 has a direct role in alternative splicing of pre-mRNA. Via its splicing function, EWS-FLI1 imposes the expression of specific protein isoforms by Ewing sarcoma cells that affects their adhesion and migration properties, both of which are key in tumor progression and metastasis. This study not only adds significant new insights into the pathological functions of EWS-FLI1 but also suggest new therapeutic avenues for Ewing sarcoma. Specifically targeting this new function of EWS-FLI1 in splicing gives hopes for the future, for more effective and personalized treatments for Ewing sarcoma young patients.
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