OLIG2 mediates a rare targetable stem cell fate transition in sonic hedgehog medulloblastoma
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<sup>+</sup> 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.
Authors
- Robert J. Vanner (ORCID: https://orcid.org/0000-0003-1169-1778)
- Erika Luis
- Benjamin David Simons (ORCID: https://orcid.org/0000-0002-3875-7071)
- Paul Guilhamon (ORCID: https://orcid.org/0000-0001-8276-5987)
- Gregory Stein (ORCID: https://orcid.org/0000-0002-3588-8834)
- Michelle Kushida
- Jerry Fan (ORCID: https://orcid.org/0000-0002-2381-5427)
- Julia E. Jaramillo
- Lilian Lee
- Peter B. Dirks (ORCID: https://orcid.org/0000-0001-5718-6465)
- Santosh Kesari (ORCID: https://orcid.org/0000-0003-3772-6000)
- Chunying Yu (ORCID: https://orcid.org/0000-0002-7320-7876)
- Kinjal Desai (ORCID: https://orcid.org/0000-0002-3941-9584)
- Siyi Wanggou (ORCID: https://orcid.org/0000-0001-9031-9338)
- Xi Huang (ORCID: https://orcid.org/0000-0002-7177-7525)
- Hayden Selvadurai
- Jinchu Vijay (ORCID: https://orcid.org/0000-0002-7311-475X)
- Heather Whetstone
- Xuejun Li (ORCID: https://orcid.org/0000-0001-6406-4423)
Institutions
- University Health Network (CA)
- Central South University (CN)
- University of Toronto (CA)
- University of Cambridge (GB)
- Hospital for Sick Children (CA)
- The Gurdon Institute (GB)
- Princess Margaret Cancer Centre (CA)
- Brain Tumour Research (GB)
- Saint John's Health Center (US)
- Hunan Cancer Hospital (CN)
- SickKids Foundation (CA)
- Xiangya Hospital Central South University (CN)
- Wellcome Trust (GB)
- Medical Research Council (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-04
- DOI
- https://doi.org/10.1038/s41467-024-54858-y
- Citations
- 9
- Primary Topic
- Hedgehog Signaling Pathway Studies
- Type
- article
- Field-Weighted Citation Impact
- 7.25
Funders
- Cancer Research UK
- University of Toronto
- Hospital for Sick Children
- Stand Up To Cancer
- Canadian Institutes of Health Research
- Garron Family Cancer Centre