Ewing sarcoma is the second most frequent bone tumour in children, adolescents, and young adults. There is no specific treatment for this disease and the long-term survival of patients with metastatic or relapsed Ewing sarcoma is very low.
Ewing sarcoma is caused by a single oncogene that results from the fusion of two genes. Although a variety of genes may be involved, the fusion protein oncogene EWS-FLI is the most frequent . All attempts to develop experimental animal models of Ewing sarcoma in mice (expressing the EWS-FLI oncogene) have failed.
Prompted by the need for a genetically tractable model that could be used to study the disease, we have teamed up with trhe laboratory of Dr. Jaume Mora, scientific director at the IRSJD Pediatric Cancer Center Barcelona (PCCB), to engineer Drosophila transgenic strains that express a mutant variant of the human oncogene called EWS-FLIFS. Remarkably, we have found that expression of the human EWS-FLIFS protein in certain types of Drosophila cells triggers the same oncogenic pathways known to account for EWS-FLI oncogenic activity in human patients.
Building upon their new transgenic Drosophila line, we have rewired two oncogenic pathways used by EWS-FLI, such that when triggered by the presence of EWS-FLIFS, they result in the expression of a fluorescent protein that would otherwise never be expressed. Thus, rather than tumour growth, wes use fluorescence as a read-out of EWS-FLI oncogenic activity. This simple genetic trick greatly facilitates the implementation of massive genetic and chemical screens to identify “modifiers” that inhibit EWS-FLI’s oncogenic activity as inhibitors of the appearance of fluorescence.
Genetic screens based on this new model will make it possible to discover critical proteins required for EWS-FLI to exert its oncogenic function, hence expanding our knowledge of the molecular basis of the disease, as well as identifying new putative therapeutic targets. Chemical screens may identify compounds that could serve as lead molecules for the development of therapeutic drugs.