Noncanonical activation of GLI signaling in SOX2(+) cells drives medulloblastoma relapse

• Type of Material: Article
• Authors: Marzena Swiderska-Syn, Medical University of South Carolina; Júlia Mir-Pedrol, Pompeu Fabra University; Alexander Oles, Medical University of South Carolina; Olga Schleuger, Medical University of South Carolina; April D Salvador, Medical University of South Carolina; Sean M Greiner, Medical University of South Carolina; Cara Seward, Medical University of South Carolina; Fang Yang, University of Miami; Benjamin R Babcock, Emory University; Chen Shen, Georgetown University; Daniel T Wynn, Georgetown University; Avencia Sanchez-Mejias, Pompeu Fabra University; Timothy Gershon, Emory University; Vanesa Martin, University of Oviedo; Heather J McCrea, University of Miami; Kathryn G Lindsey, Medical University of South Carolina; Carsten Krieg, Medical University of South Carolina; Jeazabel Rodriguez-Blanco, Medical University of South Carolina
• Language: English
• Date: 2022-07-22
• Publisher: AMER ASSOC ADVANCEMENT SCIENCE
• Publication Version: Final Published Version
• Copyright Statement: © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1126/sciadv.abj9138
• Title of Journal or Parent Work: SCIENCE ADVANCES
• Volume: 8
• Issue: 29
• Start Page: eabj9138
• End Page: eabj9138
• Grant/Funding Information: This work was supported by the American Cancer Society Institutional Research Grant awarded to the Hollings Cancer Center: IRG-19-137-20 (to J.R.-B.), the Rally Foundation Career Development Award: 20CDN46 (to J.R.-B.), the National Institute of Neurological Disorders and Stroke of the National Institutes of Health Award K01NS119351 (to J.R.-B.), and SCTR grant UL1TR001450 (to J.R.-B.).
• Keywords: Multidisciplinary Sciences; Science & Technology - Other Topics; PROLIFERATION; LINEAGE; Science & Technology; C-MYC INHIBITOR; GROWTH; 10058-F4; RESISTANCE; SUPPRESSOR; HEDGEHOG; VISMODEGIB; BROMODOMAIN PROTEINS
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

SRY (sex determining region Y)–box 2 (SOX2)–labeled cells play key roles in chemoresistance and tumor relapse; thus, it is critical to elucidate the mechanisms propagating them. Single-cell transcriptomic analyses of the most common malignant pediatric brain tumor, medulloblastoma (MB), revealed the existence of astrocytic Sox2+ cells expressing sonic hedgehog (SHH) signaling biomarkers. Treatment with vismodegib, an SHH inhibitor that acts on Smoothened (Smo), led to increases in astrocyte-like Sox2+ cells. Using SOX2-enriched MB cultures, we observed that SOX2+ cells required SHH signaling to propagate, and unlike in the proliferative tumor bulk, the SHH pathway was activated in these cells downstream of Smo in an MYC-dependent manner. Functionally different GLI inhibitors depleted vismodegib-resistant SOX2+ cells from MB tissues, reduced their ability to further engraft in vivo, and increased symptom-free survival. Our results emphasize the promise of therapies targeting GLI to deplete SOX2+ cells and provide stable tumor remission.