Unraveling Ewing Sarcoma Tumorigenesis Originating from Patient-Derived Mesenchymal Stem Cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 2021-10, Vol.81 (19), p.4994-5006
• Main Authors: Sole, Anna, Grossetête, Sandrine, Heintzé, Maxime, Babin, Loelia, Zaïdi, Sakina, Revy, Patrick, Renouf, Benjamin, De Cian, Anne, Giovannangeli, Carine, Pierre-Eugène, Cécile, Janoueix-Lerosey, Isabelle, Couronné, Lucile, Kaltenbach, Sophie, Tomishima, Mark, Jasin, Maria, Grünewald, Thomas G P, Delattre, Olivier, Surdez, Didier, Brunet, Erika
• Format: Article
• Language: English
• Subjects: Animals; Biochemistry, Molecular Biology; Biomarkers; Cell Transformation, Neoplastic; Cells, Cultured; Computational Biology - methods; CRISPR-Cas Systems; Disease Models, Animal; Disease Susceptibility; Gene Editing; Gene Expression Profiling; Gene Rearrangement; Gene Targeting; Heterografts; Humans; Immunophenotyping; In Situ Hybridization, Fluorescence; Life Sciences; Mesenchymal Stem Cells - metabolism; Mesenchymal Stem Cells - pathology; Mice; Mutation; Sarcoma, Ewing - etiology; Sarcoma, Ewing - metabolism; Sarcoma, Ewing - pathology; Translocation, Genetic
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-20-3837

Ewing sarcoma is characterized by pathognomonic translocations, most frequently fusing with . An estimated 30% of Ewing sarcoma tumors also display genetic alterations in , , or ( ). Numerous attempts to develop relevant Ewing sarcoma models from primary human cells have been unsuccessful in faithfully recapitulating the phenotypic, transcriptomic, and epigenetic features of Ewing sarcoma. In this study, by engineering the t(11;22)(q24;q12) translocation together with a combination of SPC mutations, we generated a wide collection of immortalized cells (EWIma cells) tolerating EWSR1-FLI1 expression from primary mesenchymal stem cells (MSC) derived from a patient with Ewing sarcoma. Within this model, alterations strongly favored Ewing sarcoma oncogenicity. Xenograft experiments with independent EWIma cells induced tumors and metastases in mice, which displayed features of Ewing sarcoma. EWIma cells presented balanced but also more complex translocation profiles mimicking chromoplexy, which is frequently observed in Ewing sarcoma and other cancers. Collectively, these results demonstrate that bone marrow-derived MSCs are a source of origin for Ewing sarcoma and also provide original experimental models to investigate Ewing sarcomagenesis. SIGNIFICANCE: These findings demonstrate that Ewing sarcoma can originate from human bone-marrow-derived mesenchymal stem cells and that recurrent mutations support EWSR1-FLI1 translocation-mediated transformation.