{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T21:01:07Z","timestamp":1791925267770,"version":"4.3.4"},"reference-count":70,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"43","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2023,10,27]]},"abstract":"<jats:p>Cancers in the central nervous system resist therapies effective in other cancers, possibly due to the unique biochemistry of the human brain microenvironment composed of cerebrospinal fluid (CSF). However, the impact of CSF on cancer cells and therapeutic efficacy is unknown. Here, we examined the effect of human CSF on glioblastoma (GBM) tumors from 25 patients. We found that CSF induces tumor cell plasticity and resistance to standard GBM treatments (temozolomide and irradiation). We identified nuclear protein 1 (NUPR1), a transcription factor hampering ferroptosis, as a mediator of therapeutic resistance in CSF. NUPR1 inhibition with a repurposed antipsychotic, trifluoperazine, enhanced the killing of GBM cells resistant to chemoradiation in CSF. The same chemo-effective doses of trifluoperazine were safe for human neurons and astrocytes derived from pluripotent stem cells. These findings reveal that chemoradiation efficacy decreases in human CSF and suggest that combining trifluoperazine with standard care may improve the survival of patients with GBM.<\/jats:p>","DOI":"10.1126\/sciadv.adf1332","type":"journal-article","created":{"date-parts":[[2023,10,25]],"date-time":"2023-10-25T17:59:21Z","timestamp":1698256761000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":22,"title":["Human cerebrospinal fluid affects chemoradiotherapy sensitivities in tumor cells from patients with glioblastoma"],"prefix":"10.1126","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4552-9736","authenticated-orcid":true,"given":"Brett W.","family":"Stringer","sequence":"first","affiliation":[{"name":"South Australian Health and Medical Research Institute (SAHMRI), Laboratory for Human Neurophysiology and Genetics, Adelaide, SA, Australia."},{"name":"Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5517-5903","authenticated-orcid":true,"given":"Manam Inushi","family":"De Silva","sequence":"additional","affiliation":[{"name":"South Australian Health and Medical Research Institute (SAHMRI), Laboratory for Human Neurophysiology and Genetics, Adelaide, SA, Australia."},{"name":"Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0103-8321","authenticated-orcid":true,"given":"Zarina","family":"Greenberg","sequence":"additional","affiliation":[{"name":"South Australian Health and Medical Research Institute (SAHMRI), Laboratory for Human Neurophysiology and Genetics, Adelaide, SA, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9531-1180","authenticated-orcid":true,"given":"Alejandra","family":"Nore\u00f1a Puerta","sequence":"additional","affiliation":[{"name":"South Australian Health and Medical Research Institute (SAHMRI), Laboratory for Human Neurophysiology and Genetics, Adelaide, SA, Australia."},{"name":"Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6254-0385","authenticated-orcid":true,"given":"Robert","family":"Adams","sequence":"additional","affiliation":[{"name":"South Australian Health and Medical Research Institute (SAHMRI), Laboratory for Human Neurophysiology and Genetics, Adelaide, SA, Australia."},{"name":"Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3851-9564","authenticated-orcid":true,"given":"Bridget","family":"Milky","sequence":"additional","affiliation":[{"name":"South Australian Health and Medical Research Institute (SAHMRI), Laboratory for Human Neurophysiology and Genetics, Adelaide, SA, Australia."},{"name":"Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Zabolocki","sequence":"additional","affiliation":[{"name":"South Australian Health and Medical Research Institute (SAHMRI), Laboratory for Human Neurophysiology and Genetics, Adelaide, SA, Australia."},{"name":"Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9971-2547","authenticated-orcid":true,"given":"Mark","family":"van den Hurk","sequence":"additional","affiliation":[{"name":"South Australian Health and Medical Research Institute (SAHMRI), Laboratory for Human Neurophysiology and Genetics, Adelaide, SA, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8041-9666","authenticated-orcid":true,"given":"Lisa M.","family":"Ebert","sequence":"additional","affiliation":[{"name":"Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia."},{"name":"Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, SA, Australia."},{"name":"Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1702-1928","authenticated-orcid":true,"given":"Christine","family":"Fairly Bishop","sequence":"additional","affiliation":[{"name":"Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia."},{"name":"Flinders Medical Centre, SA Health, Adelaide, SA, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1376-4515","authenticated-orcid":true,"given":"Simon J.","family":"Conn","sequence":"additional","affiliation":[{"name":"Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9923-5149","authenticated-orcid":true,"given":"Ganessan","family":"Kichenadasse","sequence":"additional","affiliation":[{"name":"Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia."},{"name":"Flinders Medical Centre, SA Health, Adelaide, SA, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5954-7105","authenticated-orcid":true,"given":"Michael Z.","family":"Michael","sequence":"additional","affiliation":[{"name":"Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia."},{"name":"Flinders Medical Centre, SA Health, Adelaide, SA, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4256-7481","authenticated-orcid":true,"given":"Rebecca J.","family":"Ormsby","sequence":"additional","affiliation":[{"name":"Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9486-4904","authenticated-orcid":true,"given":"Santosh","family":"Poonoose","sequence":"additional","affiliation":[{"name":"Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8321-0852","authenticated-orcid":true,"given":"Cedric","family":"Bardy","sequence":"additional","affiliation":[{"name":"South Australian Health and Medical Research Institute (SAHMRI), Laboratory for Human Neurophysiology and Genetics, Adelaide, SA, Australia."},{"name":"Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.canep.2015.02.008"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa043330"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-020-00447-z"},{"key":"e_1_3_2_5_2","doi-asserted-by":"crossref","unstructured":"C. Fernandes A.\u00a0Costa L.\u00a0Osorio R.\u00a0C.\u00a0Lago P.\u00a0Linhares B.\u00a0Carvalho C.\u00a0Caeiro Current standards of care in glioblastoma therapy in Glioblastoma S.\u00a0De Vleeschouwer Ed. (Exon Publications 2017).","DOI":"10.15586\/codon.glioblastoma.2017.ch11"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noz150"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-021-00518-9"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-019-0224-7"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21613"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI89587"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2017.02.009"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-018-0006-7"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2018.00431"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1186\/1743-8454-5-10"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2015.07.027"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3921"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11515-016-1401-7"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2006.03.030"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.20193"},{"key":"e_1_3_2_20_2","first-page":"5821","article-title":"Identification of a cancer stem cell in human brain tumors","volume":"63","author":"Singh S. K.","year":"2003","unstructured":"S. K.\u00a0Singh, I. D.\u00a0Clarke, M.\u00a0Terasaki, V. E.\u00a0Bonn, C.\u00a0Hawkins, J.\u00a0Squire, P. B.\u00a0Dirks, Identification of a cancer stem cell in human brain tumors. Cancer Res. 63, 5821\u20135828 (2003).","journal-title":"Cancer Res."},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12987-022-00354-8"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2017.171"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11060-008-9609-2"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1093\/neuros\/nyz144"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00927-7"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11910-008-0058-2"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1177\/1756285616635987"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.6004\/jnccn.2020.0052"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa043331"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2016.02.008"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2018.12.010"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature20123"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2019.03.064"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2013.08.001"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.06.024"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2009.12.020"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2017.06.003"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2022.10.010"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.261982.115"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.01.076"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.3892\/ijo.2021.5201"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-20904-2"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI127223"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep39732"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.22324"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201802322RR"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-021-00662-2"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsb1194-795"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0893-133X(96)00187-X"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2014.00220"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaz2193"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2012.504"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1504393112"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-19275-x"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.624145"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04722-0"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2012.556"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2016.19"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-019-0263-3"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.00897"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.03.042"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.3349\/ymj.2021.62.9.843"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djab018"},{"key":"e_1_3_2_64_2","first-page":"CD010226","article-title":"Trifluoperazine versus placebo for schizophrenia","volume":"2014","author":"Koch K.","year":"2014","unstructured":"K.\u00a0Koch, K.\u00a0Mansi, E.\u00a0Haynes, C. E.\u00a0Adams, S.\u00a0Sampson, V. A.\u00a0Furtado, Trifluoperazine versus placebo for schizophrenia. Cochrane Database Syst. Rev. 2014, CD010226 (2014).","journal-title":"Cochrane Database Syst. Rev."},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-41277-z"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-018-0103-9"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.gpb.2022.04.008"},{"key":"e_1_3_2_69_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btw313"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3438"},{"key":"e_1_3_2_71_2","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/now247"}],"container-title":["Science Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/sciadv.adf1332","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,9]],"date-time":"2024-01-09T22:45:08Z","timestamp":1704840308000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/sciadv.adf1332"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,27]]},"references-count":70,"journal-issue":{"issue":"43","published-print":{"date-parts":[[2023,10,27]]}},"alternative-id":["10.1126\/sciadv.adf1332"],"URL":"https:\/\/doi.org\/10.1126\/sciadv.adf1332","relation":{},"ISSN":["2375-2548"],"issn-type":[{"value":"2375-2548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,27]]},"assertion":[{"value":"2022-09-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-09-21","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-10-25","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadf1332"}}