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Dormant SOX9-Positive Cells Facilitate MYC-Driven Recurrence of Medulloblastoma
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.ORCID iD: 0000-0003-4696-7703
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.ORCID iD: 0000-0003-2835-1518
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2022 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 82, no 24, p. 4586-4603Article in journal (Refereed) Published
Abstract [en]

Relapse is the leading cause of death in patients with medulloblas-toma, 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.

Place, publisher, year, edition, pages
AMER ASSOC CANCER RESEARCH , 2022. Vol. 82, no 24, p. 4586-4603
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Cancer and Oncology
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URN: urn:nbn:se:uu:diva-494638DOI: 10.1158/0008-5472.CAN-22-2108ISI: 000907019300001PubMedID: 36219398OAI: oai:DiVA.org:uu-494638DiVA, id: diva2:1729379
Funder
Swedish Cancer SocietySwedish Research Council, VR-2017-02074EU, Horizon 2020, 640275Swedish Childhood Cancer FoundationSwedish Society of MedicineThe Swedish Brain FoundationÅke Wiberg FoundationRagnar Söderbergs stiftelseKnut and Alice Wallenberg FoundationAvailable from: 2023-01-20 Created: 2023-01-20 Last updated: 2023-01-20Bibliographically approved

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Borgenvik, AnnaBolin, SaraZhao, MiaoSavov, VasilRosén, GabrielaHutter, SonjaBergström, TobiasOlsen, Thale KristinMainwaring, OliverSundström, AndersBallester Bravo, MarDang, YonglongWenz, Amelie S.Fotaki, GrammatikiKalushkova, AntoniaČančer, MatkoJernberg Wiklund, HelenaGiraud, GeraldineChen, XingqiWeishaupt, HolgerSwartling, Fredrik J.

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Borgenvik, AnnaBolin, SaraZhao, MiaoSavov, VasilRosén, GabrielaHutter, SonjaBergström, TobiasOlsen, Thale KristinMainwaring, OliverSundström, AndersBallester Bravo, MarDang, YonglongWenz, Amelie S.Fotaki, GrammatikiKalushkova, AntoniaČančer, MatkoJernberg Wiklund, HelenaGiraud, GeraldineChen, XingqiWeishaupt, HolgerSwartling, Fredrik J.
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Science for Life Laboratory, SciLifeLabNeurooncology and neurodegenerationDepartment of Immunology, Genetics and PathologyCancer precision medicineMolecular Tools and Functional Genomics
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