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Sci Adv ; 8(29): eabj9138, 2022 07 22.
Article in English | MEDLINE | ID: mdl-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 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.


Subject(s)
Brain Neoplasms , Cerebellar Neoplasms , Medulloblastoma , Cerebellar Neoplasms/genetics , Child , Hedgehog Proteins/metabolism , Humans , Medulloblastoma/genetics , Medulloblastoma/pathology , Neoplasm Recurrence, Local , SOXB1 Transcription Factors/genetics , SOXB1 Transcription Factors/metabolism , Signal Transduction , Zinc Finger Protein GLI1/metabolism
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