Noncanonical activation of GLI signaling in SOX2+ cells drives medulloblastoma relapse
Menée in vitro et à l'aide de modèles murins, cette étude met en évidence un mécanisme par lequel l'activation non canonique de la voie de signalisation du facteur de transcription GLI dans les cellules de médulloblastome surexprimant SOX2 favorise la récidive
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. Noncanonical activation of sonic hedgehog signaling drives the propagation of a SOX2+ population to promote tumor relapse.
Science Advances 2022