EWSR1/FLI1 Expression in Human Mesenchymal Stem Cells derived from Experimental Teratomas Leads to Ewing´s Sarcoma Tumorigenesis [RNA-seq]

Ewing sarcoma is an aggressive bone and soft tissue neoplasm, unique to humans, characterised by EWSR1/ETS rearrangements and whose cellular origin remains unknown. We report that human embryonic stem cells expressing EWSR1/FLI1 can form experimental teratomas. Mesenchymal stem-like cells (hMSLCs) isolated from these teratomas lack tumourigenic capacity despite retaining low levels of EWSR1/FLI1 expression. Subsequent transduction of hMSLCs with EWSR1/FLI1 results in the expression of endothelial and neural genes, the acquisition of an Ewing sarcoma transcriptional signature and the formation of tumours in the spine and in soft tissues. These lesions are frequently haemorrhagic and composed of small round cells expressing discriminating markers of Ewing sarcoma. In summary, EWSR1/FLI1 enforces an aberrant endothelial-neural hybrid transcriptome and endows in vivo transforming capacity when expressed in a highly undifferentiated mesenchymal stem cell. This new experimental approach provides a test bench to elucidate the biology of translocation-dependent prenatal tumours, ranging from leukaemia to a variety of sarcomas.