| First Author | Swiderska-Syn M | Year | 2022 |
| Journal | Sci Adv | Volume | 8 |
| Issue | 29 | Pages | eabj9138 |
| PubMed ID | 35857834 | Mgi Jnum | J:327233 |
| Mgi Id | MGI:7329514 | Doi | 10.1126/sciadv.abj9138 |
| Citation | Swiderska-Syn M, et al. (2022) Noncanonical activation of GLI signaling in SOX2(+) cells drives medulloblastoma relapse. Sci Adv 8(29):eabj9138 |
| abstractText | 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. |
