Exploring the surfaceome of Ewing sarcoma identifies a new and unique therapeutic target

The cell surface proteome of tumours mediates the interface between the transformed cells and the general micro-environment including interactions with stromal cells in the tumour niche and immune cells such as T cells. In addition, the cell surface proteome of individual cancers defines biomarkers for that tumour type and potential proteins that can be the target of antibody-mediated therapy. We have used next generation deep RNA sequencing (RNA-seq) coupled to an in-house database of genes encoding cell surface proteins (herein referred to as the surfaceome) as a tool to define a cell surface proteome of Ewing sarcoma compared with progenitor mesenchymal stem cells. This subtractive RNA-seq analysis revealed a specific surfaceome of Ewing and showed unexpectedly that the leucine-rich repeat and immunoglobulin domain protein LINGO1 is expressed on over 90% of Ewing sarcoma tumours, but not expressed in any other somatic tissue apart from the brain. We found that the LINGO1 protein acts as a gateway protein internalizing into the tumour cells when engaged by antibody and can carry antibody conjugated with drugs to kill Ewing sarcoma cells. Therefore, LINGO1 is a novel, unique and specific biomarker and drug target for the treatment of Ewing sarcoma.