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Dormant SOX9-Positive Cells Facilitate MYC-Driven Recurrence of Medulloblastoma

Lookup NU author(s): Dr Stacey Richardson, Dr Rebecca Hill, Professor Steven CliffordORCiD

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


Abstract

©2022 The Authors; Published by the American Association for Cancer Research. Relapse is the leading cause of death in patients with medulloblastoma, the most common malignant pediatric brain tumor. A better understanding of the mechanisms underlying recurrence could lead to more effective therapies for targeting tumor relapses. Here, we observed that SOX9, a transcription factor and stem cell/glial fate marker, is limited to rare, quiescent cells in high-risk medulloblastoma with MYC amplification. In paired primary-recurrent patient samples, SOX9-positive cells accumulated in medulloblastoma relapses. SOX9 expression anti-correlated with MYC expression in murine and human medulloblastoma cells. However, SOX9-positive cells were plastic and could give rise to a MYC high state. To follow relapse at the single-cell level, an inducible dual Tet model of medulloblastoma was developed, in which MYC expression was redirected in vivo from treatment-sensitive bulk cells to dormant SOX9-positive cells using doxycycline treatment. SOX9 was essential for relapse initiation and depended on suppression of MYC activity to promote therapy resistance, epithelial-mesenchymal transition, and immune escape. p53 and DNA repair pathways were downregulated in recurrent tumors, whereas MGMT was upregulated. Recurrent tumor cells were found to be sensitive to treatment with an MGMT inhibitor and doxorubicin. These findings suggest that recurrence-specific targeting coupled with DNA repair inhibition comprises a potential therapeutic strategy in patients affected by medulloblastoma relapse. SIGNIFICANCE: SOX9 facilitates therapy escape and recurrence in medulloblastoma via temporal inhibition of MYC/MYCN genes, revealing a strategy to specifically target SOX9-positive cells to prevent tumor relapse.


Publication metadata

Author(s): Borgenvik A, Holmberg KO, Bolin S, Zhao M, Savov V, Rosen G, Hutter S, Garancher A, Rahmanto AS, Bergstrom T, Olsen TK, Mainwaring OJ, Sattanino D, Verbaan AD, Rusert JM, Sundstrom A, Bravo MB, Dang Y, Wenz AS, Richardson S, Fotaki G, Hill RM, Dubuc AM, Kalushkova A, Remke M, Cancer M, Jernberg-Wiklund H, Giraud G, Chen X, Taylor MD, Sangfelt O, Clifford SC, Schuller U, Wechsler-Reya RJ, Weishaupt H, Swartling FJ

Publication type: Article

Publication status: Published

Journal: Cancer Research

Year: 2022

Volume: 82

Issue: 24

Pages: 4586-4603

Print publication date: 15/12/2022

Acceptance date: 07/10/2022

Date deposited: 12/01/2023

ISSN (print): 0008-5472

ISSN (electronic): 1538-7445

Publisher: American Association for Cancer Research

URL: https://doi.org/10.1158/0008-5472.CAN-22-2108

DOI: 10.1158/0008-5472.CAN-22-2108

PubMed id: 36219398


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Funding

Funder referenceFunder name
640275
Åke Wibergs Foundation
European Research Council - Horizon 2020
Swedish Brain Foundation
Swedish Cancer Society
Swedish Childhood Cancer Fund
Swedish Research Council
Ragnar Soderbergs Foundation,
Swedish Society of Medicine
Worldwide Cancer Research

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