journal contribution posted on 2023-03-31, 06:01 authored by Anna Borgenvik, Karl O. Holmberg, Sara Bolin, Miao Zhao, Vasil Savov, Gabriela Rosén, Sonja Hutter, Alexandra Garancher, Aldwin Suryo Rahmanto, Tobias Bergström, Thale Kristin Olsen, Oliver J. Mainwaring, Damiana Sattanino, Annemieke D. Verbaan, Jessica M. Rusert, Anders Sundström, Mar Ballester Bravo, Yonglong Dang, Amelie S. Wenz, Stacey Richardson, Grammatiki Fotaki, Rebecca M. Hill, Adrian M. Dubuc, Antonia Kalushkova, Marc Remke, Matko Čančer, Helena Jernberg-Wiklund, Géraldine Giraud, Xingqi Chen, Michael D. Taylor, Olle Sangfelt, Steven C. Clifford, Ulrich Schüller, Robert J. Wechsler-Reya, Holger Weishaupt, Fredrik J. Swartling
Supplementary Figure Legends
Barncancerfonden (Swedish Childhood Cancer Foundation)
Cancerfonden (Swedish Cancer Society)
Svenska Läkaresällskapet (SLS)
HORIZON EUROPE European Research Council (ERC)
Åke Wiberg Stiftelse (Åke Wiberg Foundation)
Ragnar Söderbergs stiftelse
Worldwide Cancer Research (WCR)
Science for Life Laboratory (SciLifeLab)
ARTICLE ABSTRACTRelapse 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.
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.