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

Anna Sole (1) , Sandrine Grossetête (2) , Maxime Heintzé (1) , Loelia Babin (1) , Sakina Zaïdi (2) , Patrick Revy (1) , Benjamin Renouf (3) , Anne de Cian (3) , Carine Giovannangeli (3) , Cécile Pierre-Eugène (2) , Isabelle Janoueix-Lerosey (2) , Lucile Couronné (1, 4) , Sophie Kaltenbach (4) , Mark Tomishima (5) , Maria Jasin (5) , Thomas G.P. Grünewald (6, 7, 8, 9) , Olivier Delattre (2) , Didier Surdez (2, 10) , Erika Brunet (1)

1 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
2 U830 - Unité de génétique et biologie des cancers
3 STRING - Structure et Instabilité des Génomes
4 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades
5 Memorial Sloane Kettering Cancer Center [New York]
6 DKFZ - German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg]
7 KITZ - Hopp Children's Cancer Center Heidelberg [Heidelber, Germany]
8 Heidelberg University Hospital [Heidelberg]
9 Heidelberg University
10 UZH - Universität Zürich [Zürich] = University of Zurich

Abstract Ewing sarcoma is characterized by pathognomonic translocations, most frequently fusing EWSR1 with FLI1. An estimated 30% of Ewing sarcoma tumors also display genetic alterations in STAG2, TP53, or CDKN2A (SPC). 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, SPC alterations strongly favored Ewing sarcoma oncogenicity. Xenograft experiments with independent EWIma cells induced tumors and metastases in mice, which displayed bona fide 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.

Domains: Biochemistry, Molecular Biology; Life Sciences [q-bio]

Anna Sole, Sandrine Grossetête, Maxime Heintzé, Loelia Babin, Sakina Zaïdi, et al.. Unraveling Ewing Sarcoma Tumorigenesis Originating from Patient-Derived Mesenchymal Stem Cells. Cancer Research, 2021, 81 (19), pp.4994-5006. ⟨10.1158/0008-5472.CAN-20-3837⟩. ⟨mnhn-03873854⟩