{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T18:24:07Z","timestamp":1790619847671,"version":"4.1.0"},"reference-count":49,"publisher":"National Academy of Sciences","issue":"9","license":[{"start":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T00:00:00Z","timestamp":1740528000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH\/NCI","award":["R01CA281682"],"award-info":[{"award-number":["R01CA281682"]}]},{"name":"NIH\/NCI","award":["R01CA260886"],"award-info":[{"award-number":["R01CA260886"]}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,3,4]]},"abstract":"<jats:p>Glioblastoma (GBM) is the deadliest brain cancer in adults, and all patients succumb to the tumor. While surgery followed by chemoradiotherapy delays disease progression, these treatments do not lead to tumor control, and targeted therapies or biologics have failed to further improve survival. Utilizing a transient radiation-induced state of multipotency, we used the adenylcyclase activator forskolin to alter the fate of irradiated glioma cells. The effects of the combined treatment on neuronal marker expression, cell cycle distribution, and proliferation were studied. Gene expression profiling was conducted using bulk RNA-seq. Changes in cell populations were investigated using single-cell RNA-seq. Effects on glioma stem cells (GSCs) were studied in extreme limiting dilution assays, and the effects on median survival were studied in both syngeneic and PDOX mouse models of GBM. The combined treatment induced the expression of neuronal markers in glioma cells, reduced proliferation, and led to a distinct gene expression profile. scRNA-seq revealed that the combined treatment forced glioma cells into a microglia- and neuron-like phenotype. In vivo, this treatment led to a loss of GSCs and prolonged median survival. Collectively, our data suggest that revisiting a differentiation therapy with forskolin in combination with radiation could lead to clinical benefit.<\/jats:p>","DOI":"10.1073\/pnas.2415557122","type":"journal-article","created":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T13:47:21Z","timestamp":1740577641000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":12,"title":["Radiation-induced cellular plasticity primes glioblastoma for forskolin-mediated differentiation"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8692-7530","authenticated-orcid":false,"given":"Ling","family":"He","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, David Geffen School of Medicine at University of California","place":["Los Angeles"]},{"name":"Jonsson Comprehensive Cancer Center at University of California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7015-9027","authenticated-orcid":false,"given":"Daria","family":"Azizad","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry at University of California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kruttika","family":"Bhat","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, David Geffen School of Medicine at University of California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2956-3304","authenticated-orcid":false,"given":"Angeliki","family":"Ioannidis","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, David Geffen School of Medicine at University of California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carter J.","family":"Hoffmann","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, David Geffen School of Medicine at University of California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evelyn","family":"Arambula","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, David Geffen School of Medicine at University of California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mansoureh","family":"Eghbali","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology at University of California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4625-6899","authenticated-orcid":false,"given":"Aparna","family":"Bhaduri","sequence":"additional","affiliation":[{"name":"Jonsson Comprehensive Cancer Center at University of California","place":["Los Angeles"]},{"name":"Department of Biological Chemistry at University of California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3779-4540","authenticated-orcid":false,"given":"Harley I.","family":"Kornblum","sequence":"additional","affiliation":[{"name":"Jonsson Comprehensive Cancer Center at University of California","place":["Los Angeles"]},{"name":"Neuropsychiatric Institute-Semel Institute for Neuroscience and Human Behavior at University of California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4067-9751","authenticated-orcid":false,"given":"Frank","family":"Pajonk","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, David Geffen School of Medicine at University of California","place":["Los Angeles"]},{"name":"Jonsson Comprehensive Cancer Center at University of California","place":["Los Angeles"]},{"name":"Department of Neurosurgery, David Geffen School of Medicine at University of California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,2,26]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2036535100"},{"key":"e_1_3_4_2_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. Singh , Identification of a cancer stem cell in human brain tumors. Cancer Res. 63, 5821\u20135828 (2003).","journal-title":"Cancer Res."},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature05236"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4401872"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/cmi.2017.159"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-014-2046-y"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.235515.113"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4661"},{"key":"e_1_3_4_9_2","first-page":"8492","article-title":"The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces differentiation of human breast cancer cells","volume":"61","author":"Munster P. N.","year":"2001","unstructured":"P. N. Munster , The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces differentiation of human breast cancer cells. Cancer Res. 61, 8492\u20138497 (2001).","journal-title":"Cancer Res."},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.11273"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2018.12.002"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature16466"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-19-1242"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/stem.1058"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1920154117"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2015.146"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.14230"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-33943-0"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2012.237"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1014041108"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1529"},{"key":"e_1_3_4_22_2","first-page":"1","article-title":"Forskolin: Its biological and chemical properties","volume":"20","author":"Seamon K. B.","year":"1986","unstructured":"K. B. Seamon, J. W. Daly, Forskolin: Its biological and chemical properties. Adv. Cyclic Nucleotide Protein Phosphorylation Res. 20, 1\u2013150 (1986).","journal-title":"Adv. Cyclic Nucleotide Protein Phosphorylation Res."},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.133.3.1283"},{"key":"e_1_3_4_24_2","unstructured":"F. Pajonk L. He Radiation-induced cellular plasticity primes glioblastoma for forskolin-mediated differentiation [bulk RNA-seq]. Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi. Deposited 30 December 2024."},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1093\/milmed\/167.suppl_1.66"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-0716-3373-1_17"},{"key":"e_1_3_4_27_2","unstructured":"F. Pajonk L. He Radiation-induced cellular plasticity primes glioblastoma for forskolin-mediated differentiation [Day 5]. Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi. Deposited 30 December 2024."},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2019.11.015"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1106704108"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-014-3051-2"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-020-0591-3"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.265595.120"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1089\/105072503770867228"},{"key":"e_1_3_4_34_2","unstructured":"F. Pajonk L. He Radiation-induced cellular plasticity primes glioblastoma for forskolin-mediated differentiation [Day21]. Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi. Deposited 30 December 2024."},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btad577"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1134\/S1607672916050173"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djab018"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.radonc.2021.05.027"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1002\/embr.201338254"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.02.030"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-09-1800"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1005743707803"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1005765915288"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-1529"},{"key":"e_1_3_4_45_2","first-page":"165","article-title":"Up-regulation of the cAMP\/PKA pathway inhibits proliferation, induces differentiation, and leads to apoptosis in malignant gliomas","volume":"78","author":"Chen T. C.","year":"1998","unstructured":"T. C. Chen, D. R. Hinton, R. Zidovetzki, F. M. Hofman, Up-regulation of the cAMP\/PKA pathway inhibits proliferation, induces differentiation, and leads to apoptosis in malignant gliomas. Lab. Invest 78, 165\u2013174 (1998).","journal-title":"Lab. Invest"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.490170207"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-022-04957-9"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-21-1059"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/now045"}],"updated-by":[{"DOI":"10.1073\/pnas.2506044122","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2025,4,7]],"date-time":"2025-04-07T00:00:00Z","timestamp":1743984000000}}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2415557122","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T13:47:47Z","timestamp":1740577667000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2415557122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,26]]},"references-count":49,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2025,3,4]]}},"alternative-id":["10.1073\/pnas.2415557122"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2415557122","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,26]]},"assertion":[{"value":"2024-08-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-15","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-26","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2415557122"}}