Radiation-induced extracellular vesicle (EV) release of miR-603 promotes IGF1-mediated stem cell state in glioblastomas

Valya Ramakrishnan, Beibei Xu, Johnny Akers, Thien Nguyen, Jun Ma, Sanjay Dhawan, Jianfang Ning, Ying Mao, Wei Hua, Efrosini Kokkoli, Frank Furnari, Bob S. Carter, Clark C. Chen

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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: microRNA (miRNA) profiling was performed using matched pre- and post-radiation treatment glioblastoma specimens from the same patients. All specimens harbored unmethylated O6-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).

Original languageEnglish (US)
Article number102736
JournalEBioMedicine
Volume55
DOIs
StatePublished - May 2020

Bibliographical note

Funding Information:
We thank Drs. Subree Subramanian, David Largaespada, Tomoyuki Koga, and Ming Li for careful review of this manuscript. The work is supported by NIH 1R01NS097649-01, NIH 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). Funders did not have any role in study design, data collection, data analysis, interpretation, or writing of the report. Conceptualization, V.R. B.X. and C.C.C.; Methodology, V.R. B.X. and C.C.C.; Investigation, V.R. and B.X.; Writing ? Original Draft, B.X. and C.C.C.; Writing ? Review & Editing, V.R. J.A. T.N. J.M. S.D. J.N. Y.M. W.H. E.K. F.F. B.S.C. and C.C.C.; Funding Acquisition, C.C.C.; Resources, Y.M. W.H. F.F. and B.S.C.; Supervision, C.C.C.

Funding Information:
The work is supported by NIH 1R01NS097649-01 , NIH 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). Funders did not have any role in study design, data collection, data analysis, interpretation, or writing of the report.

Publisher Copyright:
© 2020 The Authors

Keywords

  • Acquired radiation resistance
  • Extracellular vesicles
  • Glioblastoma stem-cell state
  • IGF1
  • MGMT
  • miR-603

PubMed: MeSH publication types

  • Journal Article

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