Alvaro G Alvarado1, Soumya M Turaga1, Pratheesh Sathyan1, Erin E Mulkearns-Hubert1, Balint Otvos1, Daniel J Silver1, James S Hale1, William A Flavahan1, Pascal O Zinn1, Maksim Sinyuk1, Meizhang Li1, Maheedhara R Guda1, Kiran K Velpula1, Andrew J Tsung1, Ichiro Nakano1, Michael A Vogelbaum1, Sadhan Majumder1, Jeremy N Rich1, Justin D Lathia1. 1. Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio (A.G.A., S.M.T., E.E.M.-H., B.O., D.J.S., J.S.H., M.S., M.L., J.D.L.); Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio (A.G.A., J.N.R., J.D.L.); Department of Genetics, The University of Texas, MD Anderson Cancer Center, Houston, Texas (P.S., P.O.Z., S.M.); Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio (W.A.F., J.N.R.); Laboratory of Biochemistry and Molecular Biology, School of Life Sciences, Yunnan University, Kunming, China (M.L.); Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, Illinois (M.R.G., K.K.V., A.J.T.); Department of Neurological Surgery, The Ohio State University, Columbus, Ohio (I.N.); Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio (M.A.V., J.N.R., J.D.L.); Case Comprehensive Cancer Center, Cleveland, Ohio (M.A.V., J.N.R., J.D.L.).
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.
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.
Authors: Justin D Lathia; Joseph Gallagher; John M Heddleston; Jialiang Wang; Christine E Eyler; Jennifer Macswords; Qiulian Wu; Amit Vasanji; Roger E McLendon; Anita B Hjelmeland; Jeremy N Rich Journal: Cell Stem Cell Date: 2010-05-07 Impact factor: 24.633
Authors: M Götte; C Mohr; C-Y Koo; C Stock; A-K Vaske; M Viola; S A Ibrahim; S Peddibhotla; Y H-F Teng; J-Y Low; K Ebnet; L Kiesel; G W Yip Journal: Oncogene Date: 2010-09-06 Impact factor: 9.867
Authors: Francesco Niola; Xudong Zhao; Devendra Singh; Ryan Sullivan; Angelica Castano; Antonio Verrico; Pietro Zoppoli; Dinorah Friedmann-Morvinski; Erik Sulman; Lindy Barrett; Yuan Zhuang; Inder Verma; Robert Benezra; Ken Aldape; Antonio Iavarone; Anna Lasorella Journal: J Clin Invest Date: 2012-12-17 Impact factor: 14.808
Authors: Tatyana N Ignatova; Valery G Kukekov; Eric D Laywell; Oleg N Suslov; Frank D Vrionis; Dennis A Steindler Journal: Glia Date: 2002-09 Impact factor: 7.452
Authors: Roger Stupp; Monika E Hegi; Warren P Mason; Martin J van den Bent; Martin J B Taphoorn; Robert C Janzer; Samuel K Ludwin; Anouk Allgeier; Barbara Fisher; Karl Belanger; Peter Hau; Alba A Brandes; Johanna Gijtenbeek; Christine Marosi; Charles J Vecht; Karima Mokhtari; Pieter Wesseling; Salvador Villa; Elizabeth Eisenhauer; Thierry Gorlia; Michael Weller; Denis Lacombe; J Gregory Cairncross; René-Olivier Mirimanoff Journal: Lancet Oncol Date: 2009-03-09 Impact factor: 41.316
Authors: Karine Loulier; Justin D Lathia; Veronique Marthiens; Jenne Relucio; Mohamed R Mughal; Sung-Chun Tang; Turhan Coksaygan; Peter E Hall; Srinivasulu Chigurupati; Bruce Patton; Holly Colognato; Mahendra S Rao; Mark P Mattson; Tarik F Haydar; Charles Ffrench-Constant Journal: PLoS Biol Date: 2009-08-18 Impact factor: 8.029
Authors: Soumya M Turaga; Daniel J Silver; Defne Bayik; Evi Paouri; Sen Peng; Adam Lauko; Tyler J Alban; Nozha Borjini; Sarah Stanko; Ulhas P Naik; Ruth A Keri; James R Connor; Jill S Barnholtz-Sloan; Joshua B Rubin; Michael Berens; Dimitrios Davalos; Justin D Lathia Journal: Neuro Oncol Date: 2020-11-26 Impact factor: 12.300
Authors: Andrew Wiechert; Caner Saygin; Praveena S Thiagarajan; Vinay S Rao; James S Hale; Nikhil Gupta; Masahiro Hitomi; Anil Belur Nagaraj; Analisa DiFeo; Justin D Lathia; Ofer Reizes Journal: Oncotarget Date: 2016-05-24
Authors: Arlet M Acanda de la Rocha; Hernando López-Bertoni; Elizabeth Guruceaga; Marisol González-Huarriz; Naiara Martínez-Vélez; Enric Xipell; Juan Fueyo; Candelaria Gomez-Manzano; Marta M Alonso Journal: PLoS One Date: 2016-09-26 Impact factor: 3.240