OLIG2 mediates a rare targetable stem cell fate transition in sonic hedgehog medulloblastoma.
Publication Title
Nat Commun
Document Type
Article
Publication Date
2-4-2025
Keywords
california; santa monica; pni; sjci
Abstract
Functional cellular heterogeneity in tumours often underlies incomplete response to therapy and relapse. Previously, we demonstrated that the growth of the paediatric brain malignancy, sonic hedgehog subgroup medulloblastoma, is rooted in a dysregulated developmental hierarchy, the apex of which is defined by characteristically quiescent SOX2+ stem-like cells. Integrating gene expression and chromatin accessibility patterns in distinct cellular compartments, we identify the transcription factor Olig2 as regulating the stem cell fate transition from quiescence to activation, driving the generation of downstream neoplastic progenitors. Inactivation of Olig2 blocks stem cell activation and tumour output. Targeting this rare OLIG2-driven proliferative programme with a small molecule inhibitor, CT-179, dramatically attenuates early tumour formation and tumour regrowth post-therapy, and significantly increases median survival in vivo. We demonstrate that targeting transition from quiescence to proliferation at the level of the tumorigenic cell could be a pivotal medulloblastoma treatment strategy.
Area of Special Interest
Cancer
Area of Special Interest
Neurosciences (Brain & Spine)
Area of Special Interest
Women & Children
Specialty/Research Institute
Neurosciences
Specialty/Research Institute
Oncology
Specialty/Research Institute
Pediatrics
DOI
10.1038/s41467-024-54858-y
