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ARF suppression by ...
ARF suppression by MYC but not MYCN confers increased malignancy of aggressive pediatric brain tumors
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- Mainwaring, Oliver (author)
- Uppsala universitet,Neuroonkologi,Science for Life Laboratory, SciLifeLab,Fredrik Swartling
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- Weishaupt, Holger (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Neuroonkologi
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- Zhao, Miao (author)
- Uppsala universitet,Neuroonkologi,Science for Life Laboratory, SciLifeLab
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- Rosén, Gabriela (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Neuroonkologi
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- Borgenvik, Anna, 1987- (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Neuroonkologi
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- Breinschmid, Laura (author)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab
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- Verbaan, Annemieke D. (author)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab
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- Richardson, Stacey (author)
- Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle upon Tyne, NE1 7RU, UK.
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- Thompson, Dean (author)
- Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle upon Tyne, NE1 7RU, UK.
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- Clifford, Steven C. (author)
- Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle upon Tyne, NE1 7RU, UK.
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- Hill, Rebecca M. (author)
- Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle upon Tyne, NE1 7RU, UK.
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- Annusver, Karl (author)
- Karolinska Institutet
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- Sundström, Anders (author)
- Uppsala universitet,Neuroonkologi,Science for Life Laboratory, SciLifeLab
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- Holmberg Olausson, Karl (author)
- Uppsala universitet,Neuroonkologi,Science for Life Laboratory, SciLifeLab
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- Kasper, Maria (author)
- Karolinska Institutet
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- Hutter, Sonja (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Neuroonkologi
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- Swartling, Fredrik J., 1975- (author)
- Uppsala universitet,Neuroonkologi,Science for Life Laboratory, SciLifeLab
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(creator_code:org_t)
- 2023-03-03
- 2023
- English.
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 14
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Abstract
Subject headings
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- Medulloblastoma, the most common malignant pediatric brain tumor, often harbors MYC amplifications. Compared to high-grade gliomas, MYC-amplified medulloblastomas often show increased photoreceptor activity and arise in the presence of a functional ARF/p53 suppressor pathway. Here, we generate an immunocompetent transgenic mouse model with regulatable MYC that develop clonal tumors that molecularly resemble photoreceptor-positive Group 3 medulloblastoma. Compared to MYCN-expressing brain tumors driven from the same promoter, pronounced ARF silencing is present in our MYC-expressing model and in human medulloblastoma. While partial Arf suppression causes increased malignancy in MYCN-expressing tumors, complete Arf depletion promotes photoreceptor-negative high-grade glioma formation. Computational models and clinical data further identify drugs targeting MYC-driven tumors with a suppressed but functional ARF pathway. We show that the HSP90 inhibitor, Onalespib, significantly targets MYC-driven but not MYCN-driven tumors in an ARF-dependent manner. The treatment increases cell death in synergy with cisplatin and demonstrates potential for targeting MYC-driven medulloblastoma.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- medulloblastoma
- group 3
- MYC
- Cdkn2a
- ARF
- HSP90
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Mainwaring, Oliv ...
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Weishaupt, Holge ...
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Zhao, Miao
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Rosén, Gabriela
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Borgenvik, Anna, ...
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Breinschmid, Lau ...
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Verbaan, Annemie ...
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Richardson, Stac ...
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Thompson, Dean
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Clifford, Steven ...
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Hill, Rebecca M.
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Annusver, Karl
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Sundström, Ander ...
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Holmberg Olausso ...
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Kasper, Maria
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Hutter, Sonja
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Swartling, Fredr ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
- Articles in the publication
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Nature Communica ...
- By the university
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Uppsala University
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Karolinska Institutet