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OLIG2 mediates a rare targetable stem cell fate transition in sonic hedgehog medulloblastoma

Author

Listed:
  • Kinjal Desai

    (The Hospital for Sick Children)

  • Siyi Wanggou

    (The Hospital for Sick Children
    Central South University)

  • Erika Luis

    (The Hospital for Sick Children
    University of Toronto)

  • Heather Whetstone

    (The Hospital for Sick Children)

  • Chunying Yu

    (The Hospital for Sick Children)

  • Robert J. Vanner

    (The Hospital for Sick Children
    University of Toronto
    University Health Network)

  • Hayden J. Selvadurai

    (The Hospital for Sick Children)

  • Lilian Lee

    (The Hospital for Sick Children)

  • Jinchu Vijay

    (The Hospital for Sick Children)

  • Julia E. Jaramillo

    (The Hospital for Sick Children)

  • Jerry Fan

    (The Hospital for Sick Children
    University of Toronto)

  • Paul Guilhamon

    (The Hospital for Sick Children)

  • Michelle Kushida

    (The Hospital for Sick Children)

  • Xuejun Li

    (Central South University)

  • Gregory Stein

    (Inc)

  • Santosh Kesari

    (Inc
    Pacific Neuroscience Institute and Saint John’s Cancer Institute at Providence Saint John’s Health Center)

  • Benjamin D. Simons

    (University of Cambridge
    University of Cambridge)

  • Xi Huang

    (The Hospital for Sick Children
    University of Toronto)

  • Peter B. Dirks

    (The Hospital for Sick Children
    University of Toronto
    University of Toronto)

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.

Suggested Citation

  • Kinjal Desai & Siyi Wanggou & Erika Luis & Heather Whetstone & Chunying Yu & Robert J. Vanner & Hayden J. Selvadurai & Lilian Lee & Jinchu Vijay & Julia E. Jaramillo & Jerry Fan & Paul Guilhamon & Mic, 2025. "OLIG2 mediates a rare targetable stem cell fate transition in sonic hedgehog medulloblastoma," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-54858-y
    DOI: 10.1038/s41467-024-54858-y
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    Cited by:

    1. Yuchen Li & Chaemin Lim & Taylor Dismuke & Daniel S. Malawsky & Sho Oasa & Zara C. Bruce & Carolin Offenhäuser & Ulrich Baumgartner & Rochelle C. J. D’Souza & Stacey L. Edwards & Juliet D. French & Lu, 2025. "Suppressing recurrence in Sonic Hedgehog subgroup medulloblastoma using the OLIG2 inhibitor CT-179," Nature Communications, Nature, vol. 16(1), pages 1-23, December.

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