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

Autor:	Borgenvik A; Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden., Holmberg KO; Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden., Bolin S; Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden., Zhao M; Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden., Savov V; Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden., Rosén G; Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden., Hutter S; Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden., Garancher A; Tumor Initiation & Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, San Diego, California., Rahmanto AS; Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden., Bergström T; Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden., Olsen TK; Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden., Mainwaring OJ; Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden., Sattanino D; Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden., Verbaan AD; Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden., Rusert JM; Tumor Initiation & Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, San Diego, California., Sundström A; Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden., Bravo MB; Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden., Dang Y; Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Biomedical Centre, Uppsala University, Uppsala, Sweden., Wenz AS; Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Biomedical Centre, Uppsala University, Uppsala, Sweden., Richardson S; Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle upon Tyne, United Kingdom., Fotaki G; Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden., Hill RM; Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle upon Tyne, United Kingdom., Dubuc AM; The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada., Kalushkova A; Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden., Remke M; The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada., Čančer M; Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden., Jernberg-Wiklund H; Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden., Giraud G; Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden., Chen X; Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Biomedical Centre, Uppsala University, Uppsala, Sweden., Taylor MD; The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada., Sangfelt O; Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden., Clifford SC; Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle upon Tyne, United Kingdom., Schüller U; Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Department of Paediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Research Institute Children's Cancer Center Hamburg, Hamburg, Germany., Wechsler-Reya RJ; Tumor Initiation & Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, San Diego, California., Weishaupt H; Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden., Swartling FJ; Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2022 Dec 16; Vol. 82 (24), pp. 4586-4603.
DOI:	10.1158/0008-5472.CAN-22-2108
Abstrakt:	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. (©2022 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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