{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T12:27:22Z","timestamp":1792672042076,"version":"4.5.0"},"reference-count":85,"publisher":"National Academy of Sciences","issue":"13","license":[{"start":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T00:00:00Z","timestamp":1774483200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100019822","name":"UMB | Institute for Clinical and Translational Research, University of Maryland, Baltimore","doi-asserted-by":"publisher","award":["949"],"award-info":[{"award-number":["949"]}],"id":[{"id":"10.13039\/100019822","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":[[2026,3,31]]},"abstract":"<jats:p>\n                    Drug chemoresistance remains a major reason of treatment failure in cancer patients. In head and neck squamous cell carcinoma (HNSCC), the seventh most common cancer worldwide, cisplatin chemotherapy remains the gold standard for advanced tumors but often faces loss of responsiveness and the drawback of relapse. We previously showed that the metabolic and angiogenic factor angiopoietin-like 4 (ANGPTL4) is a molecular biomarker of oral dysplasia and HNSCC. We also found that through interaction with Neuropilin 1 (NRP1), ANGPTL4 activates proliferative and migratory pathways that contribute to HNSCC development. Using HNSCC xenografts, patient tumor-derived organoids, tumor spheroids, and HNSCC cell lines, CAL27, HN13, and HN4, here we provide evidence of the role of ANGPTL4 in the development of platinum-based chemoresistance in HNSCC through the promotion of DNA damage response (DDR) and homologous recombination (HR). ANGPTL4 enhanced these mechanisms by promoting phosphorylation of RAD51 recombinase in Tyr\n                    <jats:sup>315\/54<\/jats:sup>\n                    through an NRP1\/ABL1-dependent mechanism. Pharmacologic inhibition of NRP1 or ABL1 reversed ANGPTL4-mediated DDR and HR, and increased HNSCC cell death in combination with cisplatin, in vitro and in vivo. Our results reveal a role for ANGPTL4 in RAD51-dependent DNA repair and suggest that ANGPTL4\/NRP1\/ABL1\/RAD51 may serve as an alternative therapeutic target for HNSCC.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2510265123","type":"journal-article","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T17:17:27Z","timestamp":1774545447000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":4,"title":["Targeting the ANGPTL4\/NRP1\/ABL1\/RAD51 axis reverses cisplatin resistance by impairing DNA damage repair in head and neck cancer"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5814-8436","authenticated-orcid":false,"given":"Emmanuel B.","family":"Asiedu","sequence":"first","affiliation":[{"name":"Department of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland","place":["Baltimore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9743-4216","authenticated-orcid":false,"given":"Ajay","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland","place":["Baltimore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1682-5465","authenticated-orcid":false,"given":"Alexander","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland","place":["Baltimore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek Osorio","family":"Luciano","sequence":"additional","affiliation":[{"name":"Department of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland","place":["Baltimore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7887-2004","authenticated-orcid":false,"given":"Kevin","family":"Lo","sequence":"additional","affiliation":[{"name":"The Wilmer Eye Institute, Johns Hopkins University School of Medicine","place":["Baltimore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1824-6995","authenticated-orcid":false,"given":"Deepti","family":"Sharma","sequence":"additional","affiliation":[{"name":"The Wilmer Eye Institute, Johns Hopkins University School of Medicine","place":["Baltimore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland","place":["Baltimore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feyruz","family":"Rassool","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, School of Medicine, University of Maryland","place":["Baltimore"]},{"name":"Greenebaum Comprehensive Cancer Center, University of Maryland","place":["Baltimore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5441-1014","authenticated-orcid":false,"given":"Akrit","family":"Sodhi","sequence":"additional","affiliation":[{"name":"The Wilmer Eye Institute, Johns Hopkins University School of Medicine","place":["Baltimore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6354-5898","authenticated-orcid":false,"given":"Silvia","family":"Montaner","sequence":"additional","affiliation":[{"name":"Department of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland","place":["Baltimore"]},{"name":"Greenebaum Comprehensive Cancer Center, University of Maryland","place":["Baltimore"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,3,26]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1730-1"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2020.03.007"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2022.08.011"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.med.53.082901.103929"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1001065107"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2011.02.018"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.6868"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2023.110697"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1111\/jop.13545"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1042\/BSR20110102"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1097\/MOH.0000000000000580"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M900553200"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2019.05.010"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jlr.2021.100150"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1510926"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00011-023-01753-9"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1187"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1423765112"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0183320"},{"key":"e_1_3_4_20_2","first-page":"4514","article-title":"Hypoxia-inducible factor-dependent expression of angiopoietin-like 4 by conjunctival epithelial cells promotes the angiogenic phenotype of pterygia","volume":"58","author":"Meng Q.","year":"2017","unstructured":"Q. Meng , Hypoxia-inducible factor-dependent expression of angiopoietin-like 4 by conjunctival epithelial cells promotes the angiogenic phenotype of pterygia. Invest. Ophthalmol. Vis. Sci. 58, 4514\u20134523 (2017).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI120879"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamaophthalmol.2015.3723"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1217091110"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.108175"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.5483\/BMBRep.2024-0082"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-01-328716"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-019-1089-9"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2021.103327"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-11-0519"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12032-013-0680-y"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1111\/jop.12212"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2016.371"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1111\/cas.14400"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.archoralbio.2016.07.011"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1136\/jcp.2010.078600"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2022.13419"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1715715"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22010240"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-020-00224-3"},{"key":"e_1_3_4_40_2","first-page":"42","article-title":"Epidemiology, risk factors, and prevention of head and neck squamous cell carcinoma","volume":"11","author":"Barsouk A.","year":"2023","unstructured":"A. Barsouk, J. S. Aluru, P. Rawla, K. Saginala, A. Barsouk, Epidemiology, risk factors, and prevention of head and neck squamous cell carcinoma. Med. Sci. 11, 42 (2023).","journal-title":"Med. Sci."},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-18-1522"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.medj.2023.04.003"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-62703-125-7_5"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.5306\/wjco.v7.i1.106"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/92.16.1295"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.10.5858"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-genet-071719-020312"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-022-04538-w"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2009.04.044"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2017.05.020"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1604807113"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-023-05696-1"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neo.2024.101047"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-020-0776-2"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2020.03.006"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41408-023-00823-9"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2014.00004"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00195.2021"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.01.046"},{"key":"e_1_3_4_60_2","first-page":"1541","article-title":"Mechanisms involved in biological behavior changes associated with Angptl4 expression in colon cancer cell lines","volume":"27","author":"Huang X. F.","year":"2012","unstructured":"X. F. Huang, J. Han, X. T. Hu, C. He, Mechanisms involved in biological behavior changes associated with Angptl4 expression in colon cancer cell lines. Oncol. Rep. 27, 1541\u20131547 (2012).","journal-title":"Oncol. Rep."},{"key":"e_1_3_4_61_2","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2020.11768"},{"key":"e_1_3_4_62_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-023-04819-8"},{"key":"e_1_3_4_63_2","doi-asserted-by":"publisher","DOI":"10.3892\/or_00000897"},{"key":"e_1_3_4_64_2","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2013.174"},{"key":"e_1_3_4_65_2","doi-asserted-by":"publisher","DOI":"10.1038\/35056049"},{"key":"e_1_3_4_66_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-09-307256"},{"key":"e_1_3_4_67_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-018-0904-z"},{"key":"e_1_3_4_68_2","first-page":"5632164","article-title":"TAZ regulates the cisplatin resistance of epithelial ovarian cancer cells via the ANGPTL4\/SOX2 axis","volume":"2022","author":"Li C.","year":"2022","unstructured":"C. Li, Q. Wang, Y. Luo, J. Xiang, TAZ regulates the cisplatin resistance of epithelial ovarian cancer cells via the ANGPTL4\/SOX2 axis. Anal. Cell. Pathol. (Amst.). 2022, 5632164 (2022).","journal-title":"Anal. Cell. Pathol. (Amst.)."},{"key":"e_1_3_4_69_2","doi-asserted-by":"publisher","DOI":"10.4103\/jcar.JCar_20_20"},{"key":"e_1_3_4_70_2","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2016.291"},{"key":"e_1_3_4_71_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13194831"},{"key":"e_1_3_4_72_2","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21492"},{"key":"e_1_3_4_73_2","doi-asserted-by":"publisher","DOI":"10.3892\/or.2016.5116"},{"key":"e_1_3_4_74_2","doi-asserted-by":"publisher","DOI":"10.3892\/or.2013.2374"},{"key":"e_1_3_4_75_2","doi-asserted-by":"publisher","DOI":"10.2147\/IJGM.S409336"},{"key":"e_1_3_4_76_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3627"},{"key":"e_1_3_4_77_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1821194116"},{"key":"e_1_3_4_78_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-024-01422-2"},{"key":"e_1_3_4_79_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00432-018-2667-8"},{"key":"e_1_3_4_80_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.13368"},{"key":"e_1_3_4_81_2","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-000967"},{"key":"e_1_3_4_82_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2016.139"},{"key":"e_1_3_4_83_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-018-0624-2"},{"key":"e_1_3_4_84_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1903765116"},{"key":"e_1_3_4_85_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2024.103234"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2510265123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T17:18:06Z","timestamp":1774545486000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2510265123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,26]]},"references-count":85,"journal-issue":{"issue":"13","published-print":{"date-parts":[[2026,3,31]]}},"alternative-id":["10.1073\/pnas.2510265123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2510265123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,26]]},"assertion":[{"value":"2025-05-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-26","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2510265123"}}