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Exploring the surfaceome of Ewing sarcoma identifies a new and unique therapeutic target
Jennifer Town1, Helio Pais1, Sally Harrison2
1Medical Research Council Molecular Haematology Unit, Weatherall Institute for Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, United Kingdom;
Abstract:
The cell surface proteome of tumors mediates the interface between the transformed cells and the general microenvironment, including interactions with stromal cells in the tumor niche and immune cells such as T cells. In addition, the cell surface proteome of individual cancers defines biomarkers for that tumor 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 Ig domain protein 1 (LINGO1) is expressed in over 90% of Ewing sarcoma tumors, 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 tumor cells when engaged by antibody and can carry antibody conjugated with drugs to kill Ewing sarcoma cells. Therefore, LINGO1 is a new, unique, and specific biomarker and drug target for the treatment of Ewing sarcoma.
Insights
Researchers identified leucine-rich repeat and Ig domain protein 1 (LINGO1) as a unique biomarker and drug target for Ewing sarcoma. This cell surface protein is highly expressed in tumors, offering a new therapeutic avenue.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- The tumor cell surface proteome is crucial for tumor microenvironment interactions and serves as a source of biomarkers and therapeutic targets.
- Antibody-mediated therapies require specific cell surface proteins for targeted drug delivery.
Purpose of the Study:
- To define the cell surface proteome of Ewing sarcoma and identify novel biomarkers and therapeutic targets.
- To compare the Ewing sarcoma surfaceome with that of progenitor mesenchymal stem cells.
Main Methods:
- Utilized next-generation deep RNA sequencing (RNA-seq) combined with a custom database of cell surface protein genes.
- Performed subtractive analysis to identify proteins specific to Ewing sarcoma.
Main Results:
- Identified a distinct cell surface proteome for Ewing sarcoma.
- Discovered high expression (over 90%) of leucine-rich repeat and Ig domain protein 1 (LINGO1) in Ewing sarcoma tumors, with minimal expression in other somatic tissues (except the brain).
- Demonstrated that LINGO1 internalizes upon antibody engagement and can facilitate antibody-drug conjugate delivery for targeted cancer cell killing.
Conclusions:
- LINGO1 is a novel, specific biomarker for Ewing sarcoma.
- LINGO1 represents a promising therapeutic target for antibody-mediated drug delivery in Ewing sarcoma treatment.
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