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PDF, English (Functional spatial genomics uncover a fusion-regulated and clinically relevant driver of metastasis in Ewing sarcoma - Veronika Bursic) Download (5MB) | Terms of use

Abstract

Metastasis is the major negative prognostic factor across cancer entities, yet how driver oncogenes shape transcriptional programs facilitating metastatic spread is poorly understood. In Ewing sarcoma (EwS), a highly aggressive pediatric soft-tissue and bone sarcoma, driven by chimeric FET::ETS transcription factors, low activity of the fusion oncoproteins are thought to promote metastasis, yet, the underlying mechanisms and key downstream effectors still remain largely elusive. Therefore, a spatial functional genomics approach in the EwS model identified for the first time that FET::ETS-low activity signature is localized at the invasive front of patient’s tumor and is associated with the transcriptional induction of the multifunctional shuttle LIM domain only protein 7 (LMO7). Integrating these data with clinical information showed that high LMO7 expression levels are associated with worse prognosis and the development of metastatic disease. Gene network analyses of transcriptomic data from patient-derived tumors as well as functional proteogenomic analyses of EwS cell lines with/without conditional RNA-interference-mediated knockdown of LMO7, highlight this gene as a regulatory hub involved in multiple pro-metastatic processes including epithelial-to-mesenchymal transition and cytoskeleton remodeling. Functional experiments prove that LMO7 silencing decreases the capacity of EwS cells for clonogenic growth and migration in vitro, which is mirrored by reduced primary tumor growth and complete absence of metastatic burden in vivo. In sum, these results identify LMO7 as clinically relevant key downstream regulator of FET::ETS fusions in EwS and provide an example of how the integration of functional, spatial and clinical data can shed light on how oncogenes promote metastasis in cancer.