Ewing sarcoma is the second most common bone malignancy in children and young 
adults. It is driven by oncogenic fusion proteins (i.e. EWS/FLI1) acting as 
aberrant transcription factors that upregulate and downregulate target genes, 
leading to cellular transformation. Thus, identificating these target genes and 
understanding their contribution to Ewing sarcoma tumorigenesis are key for the 
development of new therapeutic strategies. In this study we show that lysyl 
oxidase (LOX), an enzyme involved in maintaining structural integrity of the 
extracellular matrix, is downregulated by the EWS/FLI1 oncoprotein and in 
consequence it is not expressed in Ewing sarcoma cells and primary tumors. Using 
a doxycycline inducible system to restore LOX expression in an Ewing sarcoma 
derived cell line, we showed that LOX displays tumor suppressor activities. 
Interestingly, we showed that the tumor suppressor activity resides in the 
propeptide domain of LOX (LOX-PP), an N-terminal domain produced by proteolytic 
cleavage during the physiological processing of LOX. Expression of LOX-PP 
reduced cell proliferation, cell migration, anchorage-independent growth in soft 
agar and formation of tumors in immunodeficient mice. By contrast, the 
C-terminal domain of LOX, which contains the enzymatic activity, had the 
opposite effects, corroborating that the tumor suppressor activity of LOX is 
mediated exclusively by its propeptide domain. Finally, we showed that LOX-PP 
inhibits ERK/MAPK signalling pathway, and that many pathways involved in cell 
cycle progression were significantly deregulated by LOX-PP, providing a 
mechanistic explanation to the cell proliferation inhibition observed upon 
LOX-PP expression. In summary, our observations indicate that deregulation of 
the LOX gene participates in Ewing sarcoma development and identify LOX-PP as a 
new therapeutic target for one of the most aggressive paediatric malignancies. 
These findings suggest that therapeutic strategies based on the administration 
of LOX propeptide or functional analogues could be useful for the treatment of 
this devastating paediatric cancer.