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Author Notes:

Jezabel Rodriguez-Blanco, rblanco@musc.edu

Conceptualization: J.R.-B. and H.J.M. Methodology/investigation/visualization: M.S.-S., A.O., A.D.S., S.M.G., O.S., C.Se., C. Sh., C.K., J.R.-B., F.Y., D.T.W., and K.G.L. Animal studies: M.S.-S. and J.R.-B. Bioinformatic analyses: J.M.P., B.R.B., A.S.-M., T.R.G., and J.R.-B. Supervision: J.R.-B. Writing: J.R.-B., H.J.M., V.M., and J.M.P.

I thank my postdoctoral mentor, Dr. D. Robbins, for training during the years spent in his laboratory and for providing advice during the completion of this manuscript. We also thank Dr. D. Guttridge, Dr. D. Wang, Dr. M. Roussel, Dr. W. Weiss, Dr. R. Wechsler-Reya, and Taylor for providing insights during discussions regarding this manuscript. We would also like to thank the Translational Science Shared Resource at Hollings Cancer Center (supported by a P30 CA138313) for their work on tissue processing. Schematics were created using BioRender.com.

The authors declare that they have no competing interests.

Subject:

Research Funding:

This work was supported by the American Cancer Society Institutional Research Grant awarded to the Hollings Cancer Center: IRG-19-137-20 (to J.R.-B.), the Rally Foundation Career Development Award: 20CDN46 (to J.R.-B.), the National Institute of Neurological Disorders and Stroke of the National Institutes of Health Award K01NS119351 (to J.R.-B.), and SCTR grant UL1TR001450 (to J.R.-B.).

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • C-MYC INHIBITOR
  • BROMODOMAIN PROTEINS
  • HEDGEHOG
  • GROWTH
  • PROLIFERATION
  • RESISTANCE
  • VISMODEGIB
  • 10058-F4
  • LINEAGE
  • SUPPRESSOR

Noncanonical activation of GLI signaling in SOX2(+) cells drives medulloblastoma relapse

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Journal Title:

SCIENCE ADVANCES

Volume:

Volume 8, Number 29

Publisher:

, Pages eabj9138-eabj9138

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/).
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