{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T16:31:27Z","timestamp":1781109087020,"version":"3.54.1"},"reference-count":59,"publisher":"National Academy of Sciences","issue":"4","license":[{"start":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T00:00:00Z","timestamp":1737504000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000884","name":"Cancer Research Institute","doi-asserted-by":"publisher","award":["n\/a"],"award-info":[{"award-number":["n\/a"]}],"id":[{"id":"10.13039\/100000884","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005294","name":"Massachusetts General Hospital","doi-asserted-by":"publisher","award":["n\/a"],"award-info":[{"award-number":["n\/a"]}],"id":[{"id":"10.13039\/100005294","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100002553","name":"Aid for Cancer Research","doi-asserted-by":"publisher","award":["n\/a"],"award-info":[{"award-number":["n\/a"]}],"id":[{"id":"10.13039\/100002553","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005294","name":"Massachusetts General Hospital","doi-asserted-by":"publisher","award":["n\/a"],"award-info":[{"award-number":["n\/a"]}],"id":[{"id":"10.13039\/100005294","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004543","name":"China Scholarship Council","doi-asserted-by":"publisher","award":["201406380077"],"award-info":[{"award-number":["201406380077"]}],"id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001545","name":"Children's Tumor Foundation","doi-asserted-by":"publisher","award":["n\/a"],"award-info":[{"award-number":["n\/a"]}],"id":[{"id":"10.13039\/100001545","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,1,28]]},"abstract":"<jats:p>Ependymoma (EPN) is a common form of brain tumor in children, often resistant to available cytotoxic therapies. Molecular profiling studies have led to a better understanding of EPN subtypes and revealed a critical role of oncogenes ZFTA\u2013RELA fusion and EPHB2 in supratentorial ependymoma (ST-EPN). However, the immune system\u2019s role in tumor progression and response to therapy remains poorly understood. New treatments for various molecular subtypes of EPN are desperately needed. Using ST-EPN-ZFTA subtype-specific syngeneic mouse models, we found an increased frequency of M2-like tumor-associated macrophages (TAMs), which proportionally increased with tumor size during tumor progression. Transcriptomic profiling of ST-EPN-ZFTA and analysis of a human EPN dataset revealed multiple protein kinases as potential druggable targets. By matching transcriptomic signatures with the target spectrum of FDA-approved drugs, we found that the multikinase inhibitor dasatinib potently inhibited the growth of EPN both in vitro and in vivo, mainly through blocking EPHB2 and ABL1. Treatment with dasatinib reprogrammed the EPN immune microenvironment by polarizing TAMs toward an M1-like phenotype and increasing CD8 T cell activation. Furthermore, dasatinib treatment induced complete regression of established EPN tumors in 78% of the animals and protected survivors against tumor recurrence. Depletion of CD8 cells compromised the durability of EPN responses and reduced overall survival. These data indicate that dasatinib has the potential to be an effective therapy for ST-EPN-ZFTA molecular subgroup of EPN and support further investigation of dasatinib in clinical trials.<\/jats:p>","DOI":"10.1073\/pnas.2319474122","type":"journal-article","created":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T10:54:23Z","timestamp":1737543263000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":6,"title":["Targeting EPHB2\/ABL1 restores antitumor immunity in preclinical models of ependymoma"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6358-0765","authenticated-orcid":false,"given":"Jun","family":"Ren","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8285-8024","authenticated-orcid":false,"given":"Zohreh","family":"Amoozgar","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor P.","family":"Uccello","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pin-Ji","family":"Lei","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhui","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1272-8184","authenticated-orcid":false,"given":"William W.","family":"Ho","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peigen","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alisha","family":"Kardian","sequence":"additional","affiliation":[{"name":"Center of Excellence in Neuro-Oncology Sciences, St Jude Children\u2019s Research Hospital","place":["Memphis"]},{"name":"Neurobiology and Brain Tumor Program, St Jude Children\u2019s Research Hospital","place":["Memphis"]},{"name":"Department of Developmental Neurobiology, St Jude Children\u2019s Research Hospital","place":["Memphis"]},{"name":"Cancer and Cell Biology Program, Baylor College of Medicine","place":["Houston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen C.","family":"Mack","sequence":"additional","affiliation":[{"name":"Center of Excellence in Neuro-Oncology Sciences, St Jude Children\u2019s Research Hospital","place":["Memphis"]},{"name":"Neurobiology and Brain Tumor Program, St Jude Children\u2019s Research Hospital","place":["Memphis"]},{"name":"Department of Developmental Neurobiology, St Jude Children\u2019s Research Hospital","place":["Memphis"]},{"name":"Cancer and Cell Biology Program, Baylor College of Medicine","place":["Houston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7065-8797","authenticated-orcid":false,"given":"Dan G.","family":"Duda","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7571-3548","authenticated-orcid":false,"given":"Rakesh K.","family":"Jain","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,1,22]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-021-00433-2"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11060-019-03255-3"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awm046"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2007.15.9970"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noaa276"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2015.04.002"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09173"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-019-02056-2"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.1994.77"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01473"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2022.788587"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.10122"},{"key":"e_1_3_4_13_2","first-page":"455","article-title":"Coexpression of transcripts encoding EPHB receptor protein tyrosine kinases and their ephrin-B ligands in human small cell lung carcinoma","volume":"5","author":"Tang X. X.","year":"1999","unstructured":"X. X. Tang, G. M. Brodeur, B. G. Campling, N. Ikegaki, Coexpression of transcripts encoding EPHB receptor protein tyrosine kinases and their ephrin-B ligands in human small cell lung carcinoma. Clin. Cancer Res. 5, 455\u2013460 (1999).","journal-title":"Clin. Cancer Res."},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/1096-911X(20010101)36:1<80::AID-MPO1019>3.0.CO;2-N"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-20-1066"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/neuros\/nyy239"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature25169"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-20-1052"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-20-0963"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature13109"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M115.053421"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.0014-2956.2001.02473.x"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1080\/10428190801896103"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41417-019-0122-x"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-02-140665"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1007\/s003810050544"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.20355"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1006294102611"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1525360113"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0008316"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2012.46.8280"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2005.09.001"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btr625"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2105323118"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2010.30.7231"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2010.08.014"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00432-013-1488-z"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.27462"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0122555"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3124"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.960738"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMcibr1914890"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.4103\/glioma.glioma_17_21"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells12101374"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11060-018-2791-y"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22158098"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-016-1643-0"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep09248"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3563"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2008.86"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2015.07.004"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2022.05.016"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature23465"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2008.237"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-16-0061-T"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2008.07433.x"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/nop056"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12264-021-00640-9"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.05.031"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2319474122","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T10:54:57Z","timestamp":1737543297000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2319474122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,22]]},"references-count":59,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,1,28]]}},"alternative-id":["10.1073\/pnas.2319474122"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2319474122","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,22]]},"assertion":[{"value":"2023-11-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-12-18","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-22","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2319474122"}}