Coordination of self-renewal in glioblastoma by integration of adhesion and microRNA signaling. Issue 5 (15th September 2015)

• Record Type: Journal Article
• Authors: Alvarado, Alvaro G.; Turaga, Soumya M.; Sathyan, Pratheesh; Mulkearns-Hubert, Erin E.; Otvos, Balint; Silver, Daniel J.; Hale, James S.; Flavahan, William A.; Zinn, Pascal O.; Sinyuk, Maksim; Li, Meizhang; Guda, Maheedhara R.; Velpula, Kiran K.; Tsung, Andrew J.; Nakano, Ichiro; Vogelbaum, Michael A.; Majumder, Sadhan; Rich, Jeremy N.; Lathia, Justin D.
• Is Part Of: Neuro-oncology. Volume 18:Issue 5(2016:May)
• Page Start: 656
• Page End: 666
• Publication Date: 2015-09-15
• Subjects: cancer stem cell -- glioblastoma -- JAM-A -- miR-145; Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/nov196
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Background: Cancer stem cells (CSCs) provide an additional layer of complexity for tumor models and targets for therapeutic development. The balance between CSC self-renewal and differentiation is driven by niche components including adhesion, which is a hallmark of stemness. While studies have demonstrated that the reduction of adhesion molecules, such as integrins and junctional adhesion molecule-A (JAM-A), decreases CSC maintenance. The molecular circuitry underlying these interactions has yet to be resolved. Methods: MicroRNA screening predicted that microRNA-145 (miR-145) would bind to JAM-A. JAM-A overexpression in CSCs was evaluated both in vitro (proliferation and self-renewal) and in vivo (intracranial tumor initiation). miR-145 introduction into CSCs was similarly assessed in vitro. Additionally, The Cancer Genome Atlas dataset was evaluated for expression levels of miR-145 and overall survival of the different molecular groups. Results: Using patient-derived glioblastoma CSCs, we confirmed that JAM-A is suppressed by miR-145. CSCs expressed low levels of miR-145, and its introduction decreased self-renewal through reductions in AKT signaling and stem cell marker (SOX2, OCT4, and NANOG) expression; JAM-A overexpression rescued these effects. These findings were predictive of patient survival, with a JAM-A/miR-145 signature robustly predicting poor patient prognosis. Conclusions: Our results link CSC-specific niche signaling to a microRNA regulatory network that is altered in glioblastoma and can be targeted to attenuate CSC self-renewal.