Dormant SOX9-positive cells facilitate MYC-driven recurrence of medulloblastoma
Cancer Res. 2022 Oct 11:CAN-22-2108. doi: 10.1158/0008-5472.CAN-22-2108. Online ahead of print.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, while 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 wi...
Source: Cell Research - Category: Cytology Authors: Anna Borgenvik Karl O Holmberg Sara Bolin Miao Zhao Vasil Savov Gabriela Ros én Sonja Hutter Alexandra Garancher Aldwin Suryo Rahmanto Tobias Bergstr öm Thale Kristin Olsen Oliver J Mainwaring Damiana Sattanino Annemieke D Verbaan Jessica M Rusert Ander Source Type: research
More News: Brain | Brain Cancers | Brain Tumor | Cancer | Cancer & Oncology | Cytology | Damiana | Doxycycline | Epithelial Cancer | Gastroschisis Repair | Medulloblastoma | Neurology | Pediatrics | Stem Cell Therapy | Stem Cells