Noncanonical activation of GLI signaling in SOX2 cells drives medulloblastoma relapse.

Chen Shen, Jezabel Rodriguez-Blanco, Carsten Krieg, Kathryn G Lindsey, Heather J McCrea, Vanesa Martin, Timothy R Gershon, Avencia Sanchez-Mejias, Daniel T Wynn, Marzena Swiderska-Syn, Benjamin R Babcock, Fan Yang, Cara Seward, Sean M Greiner, April D Salvador, Olga Schleuger, Alexander Oles, Júlia Mir-Pedrol

Journal: Science advances 2022;8(29):eabj9138

PMID: 35857834

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 cells expressing sonic hedgehog (SHH) signaling biomarkers. Treatment with vismodegib, an SHH inhibitor that acts on Smoothened (Smo), led to increases in astrocyte-like 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.

Address: Darby Children's Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA.; Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona 08002, Spain.; Molecular Oncology Program, The Dewitt Daughtry Family Department of Surgery, University of Miami, Miami, FL 33136, USA.; Lowance Center for Human Immunology, Department of Medicine, Emory University, Atlanta, GA 30322, USA.; Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA.; Department of Anatomy and Cell Biology, University of Oviedo, Oviedo, Asturias 33006, Spain.; Department of Clinical Neurological Surgery, University of Miami, Miami, FL 33136, USA.; Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
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