{"doi":"10.1016/j.ebiom.2020.102736","title":"Radiation-induced extracellular vesicle (EV) release of miR-603 promotes IGF1-mediated stem cell state in glioblastomas","abstract":"BACKGROUND: Recurrence after radiation therapy is nearly universal for glioblastomas, the most common form of adult brain cancer. The study aims to define clinically pertinent mechanisms underlying this recurrence. METHODS: -methylguanine-DNA methyltransferase promoters (umMGMT) and wild-type isocitrate dehydrogenase (wtIDH). The most altered miRNA, miR-603, was characterized. FINDINGS: While nearly all miRNAs remained unchanged after treatment, decreased levels of few, select miRNAs in the post-treatment specimens were observed, the most notable of which involved miR-603. Unbiased profiling of miR-603 targets revealed insulin-like growth factor 1 (IGF1) and IGF1 receptor (IGF1R). Ionizing radiation (IR) induced cellular export of miR-603 through extracellular vesicle (EV) release, thereby de-repressing IGF1 and IGF1R. This de-repression, in turn, promoted cancer stem-cell (CSC) state and acquired radiation resistance in glioblastomas. Export of miR-603 additionally de-repressed MGMT, a DNA repair protein responsible for detoxifying DNA alkylating agents, to promote cross-resistance to these agents. Ectopic miR-603 expression overwhelmed cellular capacity for miR-603 export and synergized with the tumoricidal effects of IR and DNA alkylating agents. INTERPRETATION: Profiling of matched pre- and post-treatment glioblastoma specimens revealed altered homeostasis of select miRNAs in response to radiation. Radiation-induced EV export of miR-603 simultaneously promoted the CSC state and up-regulated DNA repair to promote acquired resistance. These effects were abolished by exogenous miR-603 expression, suggesting potential for clinical translation. FUNDING: NIH 1R01NS097649-01, 9R44GM128223-02, 1R01CA240953-01, the Doris Duke Charitable Foundation Clinical Scientist Development Award, The Sontag Foundation Distinguished Scientist Award, the Kimmel Scholar Award, and BWF 1006774.01 (C.C.C).","journal":"EBioMedicine","year":2020,"id":65130,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":62,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9418,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":344535,"name":"Beibei Xu","orcid":"0000-0002-7150-4375","position":1,"is_corresponding":false},{"id":346347,"name":"Johnny Akers","orcid":null,"position":2,"is_corresponding":false},{"id":344536,"name":"Thien Nguyen","orcid":"0009-0009-6782-7479","position":3,"is_corresponding":false},{"id":344537,"name":"Jun Ma","orcid":"0000-0003-0427-8205","position":4,"is_corresponding":false},{"id":252737,"name":"Sanjay Dhawan","orcid":null,"position":5,"is_corresponding":false},{"id":271742,"name":"Jianfang Ning","orcid":"0000-0001-5199-7742","position":6,"is_corresponding":false},{"id":344538,"name":"Ying Mao","orcid":"0000-0001-8055-115X","position":7,"is_corresponding":false},{"id":344539,"name":"Wei Hua","orcid":"0000-0001-6409-5078","position":8,"is_corresponding":false},{"id":344540,"name":"Efrosini Kokkoli","orcid":"0000-0001-7783-0158","position":9,"is_corresponding":false},{"id":277722,"name":"Frank B. Furnari","orcid":"0000-0003-1909-4361","position":10,"is_corresponding":false},{"id":95876,"name":"Bob S. Carter","orcid":"0000-0002-3586-1324","position":11,"is_corresponding":false},{"id":249783,"name":"Clark C. Chen","orcid":"0000-0001-9544-2570","position":12,"is_corresponding":false},{"id":346346,"name":"Valya Ramakrishnan","orcid":null,"position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":null,"created_at":"2026-07-18T21:13:23.327603Z","pmid":"32361246","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}