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

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

Borgenvik, Anna, 1987- (author): Uppsala universitet,Science for Life Laboratory, SciLifeLab,Neuroonkologi och neurodegeneration

Holmberg, Karl O. (author): Uppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab

Bolin, Sara, 1988- (author): Uppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för immunologi, genetik och patologi

Zhao, Miao (author): Uppsala universitet,Neuroonkologi och neurodegeneration,Science for Life Laboratory, SciLifeLab

Savov, Vasil (author): Uppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab

Rosén, Gabriela (author): Uppsala universitet,Science for Life Laboratory, SciLifeLab,Neuroonkologi och neurodegeneration

Hutter, Sonja (author): Uppsala universitet,Science for Life Laboratory, SciLifeLab,Neuroonkologi och neurodegeneration

Garancher, Alexandra (author): Sanford Burnham Prebys Med Discovery Inst, Tumor Initiat & Maintenance Program, San Diego, CA USA.

Rahmanto, Aldwin Suryo (author): Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden.

Bergström, Tobias, 1980- (author): Uppsala universitet,Science for Life Laboratory, SciLifeLab,Neuroonkologi och neurodegeneration

Olsen, Thale Kristin (author): Uppsala universitet,Neuroonkologi och neurodegeneration,Science for Life Laboratory, SciLifeLab

Mainwaring, Oliver (author): Uppsala universitet,Science for Life Laboratory, SciLifeLab,Neuroonkologi och neurodegeneration

Sattanino, Damiana (author): Uppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab

Verbaan, Annemieke D. (author): Uppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab

Rusert, Jessica M. (author): Sanford Burnham Prebys Med Discovery Inst, Tumor Initiat & Maintenance Program, San Diego, CA USA.

Sundström, Anders (author): Uppsala universitet,Science for Life Laboratory, SciLifeLab,Neuroonkologi och neurodegeneration

Ballester Bravo, Mar (author): Uppsala universitet,Neuroonkologi och neurodegeneration,Science for Life Laboratory, SciLifeLab

Dang, Yonglong (author): Uppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab

Wenz, Amelie S. (author): Uppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab

Richardson, Stacey (author): Newcastle Univ Ctr Canc, Wolfson Childhood Canc Res Ctr, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England.

Fotaki, Grammatiki (author): Uppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för immunologi, genetik och patologi

Hill, Rebecca M. (author): Newcastle Univ Ctr Canc, Wolfson Childhood Canc Res Ctr, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England.

Dubuc, Adrian M. (author): Hosp Sick Children, Arthur & Sonia Labatt Brain Tumor Res Ctr, Toronto, ON, Canada.

Kalushkova, Antonia (author): Uppsala universitet,Science for Life Laboratory, SciLifeLab,Cancerprecisionsmedicin

Remke, Marc (author): Hosp Sick Children, Arthur & Sonia Labatt Brain Tumor Res Ctr, Toronto, ON, Canada.

Čančer, Matko (author): Uppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab

Jernberg Wiklund, Helena (author): Uppsala universitet,Science for Life Laboratory, SciLifeLab,Cancerprecisionsmedicin

Giraud, Geraldine (author): Uppsala universitet,Science for Life Laboratory, SciLifeLab,Neuroonkologi och neurodegeneration

Chen, Xingqi (author): Uppsala universitet,Science for Life Laboratory, SciLifeLab,Molekylära verktyg och funktionsgenomik

Taylor, Michael D. (author): Hosp Sick Children, Arthur & Sonia Labatt Brain Tumor Res Ctr, Toronto, ON, Canada.

Sangfelt, Olle (author): Karolinska Institutet

Clifford, Steven C. (author): Newcastle Univ Ctr Canc, Wolfson Childhood Canc Res Ctr, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England.

Schueller, Ulrich (author): Univ Med Ctr Hamburg Eppendorf, Inst Neuropathol, Hamburg, Germany.;Univ Med Ctr Hamburg Eppendorf, Dept Paediat Hematol & Oncol, Hamburg, Germany.;Res Inst Childrens Canc Ctr Hamburg, Hamburg, Germany.

Wechsler-Reya, Robert J. (author): Sanford Burnham Prebys Med Discovery Inst, Tumor Initiat & Maintenance Program, San Diego, CA USA.

Weishaupt, Holger (author): Uppsala universitet,Science for Life Laboratory, SciLifeLab,Neuroonkologi och neurodegeneration

Swartling, Fredrik J., 1975- (author): Uppsala universitet,Science for Life Laboratory, SciLifeLab,Neuroonkologi och neurodegeneration

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AMER ASSOC CANCER RESEARCH, 2022
2022
English.
In: Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 82:24, s. 4586-4603

Related links:: https://doi.org/10.1...; show more...; https://uu.diva-port... (primary) (Raw object); https://urn.kb.se/re...; https://doi.org/10.1...; http://kipublication...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

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.

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Cancer and Oncol ...

Articles in the publication: Cancer Research

By the university: Uppsala University; Karolinska Institutet

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

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