Noncanonical activation of GLI signaling in SOX2 <sup>+</sup> cells drives medulloblastoma relapse
Marzena Swiderska‐Syn, Júlia Mir-Pedrol, Alexander Oles, Olga Schleuger, April Salvador, Sean M. Greiner, Cara Seward, Fan Yang, Benjamin Babcock, Chen Shen, Daniel T. Wynn, Avencia Sánchez-Mejías, Timothy R. Gershon, Vanesa Martı́n, Heather J. McCrea, Kathryn Lindsey, Carsten Krieg, Jezabel Rodríguez‐Blanco
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.