{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T10:54:18Z","timestamp":1793962458699,"version":"4.8.0"},"reference-count":61,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2019,1,30]],"date-time":"2019-01-30T00:00:00Z","timestamp":1548806400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Baldrick\u2019s Pediatric Cancer Dream Team Translational Research","award":["SU2CAACR-DT1113"],"award-info":[{"award-number":["SU2CAACR-DT1113"]}]},{"DOI":"10.13039\/100006535","name":"Entertainment Industry Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006535","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000043","name":"American Association for Cancer Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000043","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Ewing sarcoma (EWS) manifests one of the lowest somatic mutation rates of any cancer, leading to a scarcity of druggable mutations and neoantigens. Immunotherapeutics targeting differentially expressed cell surface antigens could provide therapeutic benefit for such tumors. Pregnancy-associated plasma protein A (PAPP-A) is a cell membrane-associated proteinase produced by the placenta that promotes fetal growth by inducing insulinlike growth factor (IGF) signaling.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>By comparing RNA expression of cell surface proteins in EWS (n\u2009=\u2009120) versus normal tissues (n\u2009=\u200942), we comprehensively characterized the surfaceome of EWS to identify highly differentially expressed molecules. Using CRISPR\/Cas-9 and anti-PAPP-A antibodies, we investigated biological roles for PAPP-A in EWS in vitro and in vivo in NSG xenograft models and performed RNA-sequencing on PAPPA knockout clones (n\u2009=\u20095) and controls (n\u2009=\u20093). All statistical tests were two-sided.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>EWS surfaceome analysis identified 11 highly differentially overexpressed genes, with PAPPA ranking second in differential expression. In EWS cell lines, genetic knockout of PAPPA and treatment with anti-PAPP-A antibodies revealed an essential survival role by regulating local IGF-1 bioavailability. MAb-mediated PAPPA inhibition diminished EWS growth in orthotopic xenografts (leg area mm2 at day 49 IgG2a control (CTRL) [n\u2009=\u200914], mean\u2009=\u2009397.0, SD\u2009=\u200986.1 vs anti-PAPP-A [n\u2009=\u200914], mean\u2009=\u2009311.7, SD\u2009=\u2009155.0; P =\u2009.03; median OS anti-PAPP-A\u2009=\u200952.5\u2009days, 95% CI\u2009=\u200946.0 to 63.0\u2009days vs IgG2a\u2009=\u200945.0\u2009days, 95% CI\u2009=\u200942.0 to 52.0\u2009days; P\u2009=\u2009.02) and improved the efficacy of anti-IGF-1R treatment (leg area mm2 at day 49 anti-PAPP-A + anti-IGF-1R [n\u2009=\u200915], mean\u2009=\u2009217.9, SD\u2009=\u2009148.5 vs IgG2a-CTRL; P\u2009&lt;\u2009.001; median OS anti-PAPP-A + anti-IGF1R\u2009=\u200963.0\u2009days, 95% CI\u2009=\u200952.0 to 67.0\u2009days vs IgG2a-CTRL; P\u2009&lt;\u2009.001). Unexpectedly, PAPPA knockout in EWS cell lines induced interferon (IFN)-response genes, including proteins associated with antigen processing\/presentation. Consistently, gene expression profiles in PAPPA-low EWS tumors were enriched for immune response pathways.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This work provides a comprehensive characterization of the surfaceome of EWS, credentials PAPP-A as a highly differentially expressed therapeutic target, and discovers a novel link between IGF-1 signaling and immune evasion in cancer, thus implicating shared mechanisms of immune evasion between EWS and the placenta.<\/jats:p><\/jats:sec>","DOI":"10.1093\/jnci\/djy209","type":"journal-article","created":{"date-parts":[[2018,11,13]],"date-time":"2018-11-13T12:43:54Z","timestamp":1542113034000},"page":"970-982","source":"Crossref","is-referenced-by-count":60,"title":["Pregnancy-Associated Plasma Protein-A (PAPP-A) in Ewing Sarcoma: Role in Tumor Growth and Immune 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R","family":"Noer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Lorette","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ladan","family":"Fazli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anya","family":"Alag","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Meltzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching","family":"Lau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheryl 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