title: Exploring the surfaceome of Ewing sarcoma identifies a new and unique therapeutic target.
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.
authors.affiliation: Medical Research Council Molecular Haematology Unit, Weatherall Institute for Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, United Kingdom;
authors.forename: Jennifer
authors.initials: J
authors.lastname: Town
authors.affiliation: Medical Research Council Molecular Haematology Unit, Weatherall Institute for Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, United Kingdom;
authors.forename: Helio
authors.initials: H
authors.lastname: Pais
authors.affiliation: Leeds Institute of Molecular Medicine, St. James's Hospital, Leeds LS9 7TF, United Kingdom;
authors.forename: Sally
authors.initials: S
authors.lastname: Harrison
authors.affiliation: Leeds Institute of Molecular Medicine, St. James's Hospital, Leeds LS9 7TF, United Kingdom;
authors.forename: Lucy F
authors.identifier: http://orcid.org/0000-0002-9550-4150
authors.initials: LF
authors.lastname: Stead
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford OX1 3AT, United Kingdom.
authors.forename: Carole
authors.initials: C
authors.lastname: Bataille
authors.affiliation: Medical Research Council Molecular Haematology Unit, Weatherall Institute for Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, United Kingdom;
authors.forename: Wilawan
authors.initials: W
authors.lastname: Bunjobpol
authors.affiliation: Medical Research Council Molecular Haematology Unit, Weatherall Institute for Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, United Kingdom;
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Medical Research Council Molecular Haematology Unit, Weatherall Institute for Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, United Kingdom; terence.rabbitts@imm.ox.ac.uk.
authors.forename: Terence H
authors.initials: TH
authors.lastname: Rabbitts
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D020543:Proteome / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics; D012512:Sarcoma, Ewing / Q000235:genetics* / Q000378:metabolism* / Q000628:therapy; D017423:Sequence Analysis, RNA
chemical_list: D014408:Biomarkers, Tumor; C482293:LINGO1 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D020543:Proteome; D012334:RNA, Neoplasm
keywords: Ewing sarcoma; LINGO1; antibody; cancer; cell surface