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; Holmberg, Karl O; Bolin, Sara; Zhao, Miao; Savov, Vasil; Rosén, Gabriela; Hutter, Sonja; Garancher, Alexandra; Suryo Rahmanto, Aldwin; Bergström, Tobias; Olsen, Thale Kristin; Mainwaring, Oliver J; Sattanino, Damiana; Verbaan, Annemieke D; Rusert, Jessica M; Sundstrom, Anders; Ballester Bravo, Mar; Dang, Yonglong; Wenz, Amelie S; Richardson, Stacey; Fotaki, Grammatiki; Hill, Rebecca M; Dubuc, Adrian M; Kalushkova, Antonia; Remke, Marc; Cancer, Matko; Jernberg-Wiklund, Helena; Giraud, Géraldine; Chen, Xingqi; Taylor, Michael D; Sangfelt, Olle; Clifford, Steven C; Schüller, Ulrich; Wechsler-Reya, Robert J; Weishaupt, Holger; Swartling, Fredrik J.
in: CANCER RES, Jahrgang 82, Nr. 24, 16.12.2022, S. 4586-4603.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Dormant SOX9-positive cells facilitate MYC-driven recurrence of medulloblastoma
AU - Borgenvik, Anna
AU - Holmberg, Karl O
AU - Bolin, Sara
AU - Zhao, Miao
AU - Savov, Vasil
AU - Rosén, Gabriela
AU - Hutter, Sonja
AU - Garancher, Alexandra
AU - Suryo Rahmanto, Aldwin
AU - Bergström, Tobias
AU - Olsen, Thale Kristin
AU - Mainwaring, Oliver J
AU - Sattanino, Damiana
AU - Verbaan, Annemieke D
AU - Rusert, Jessica M
AU - Sundstrom, Anders
AU - Ballester Bravo, Mar
AU - Dang, Yonglong
AU - Wenz, Amelie S
AU - Richardson, Stacey
AU - Fotaki, Grammatiki
AU - Hill, Rebecca M
AU - Dubuc, Adrian M
AU - Kalushkova, Antonia
AU - Remke, Marc
AU - Cancer, Matko
AU - Jernberg-Wiklund, Helena
AU - Giraud, Géraldine
AU - Chen, Xingqi
AU - Taylor, Michael D
AU - Sangfelt, Olle
AU - Clifford, Steven C
AU - Schüller, Ulrich
AU - Wechsler-Reya, Robert J
AU - Weishaupt, Holger
AU - Swartling, Fredrik J
PY - 2022/12/16
Y1 - 2022/12/16
N2 - UNLABELLED: 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.
AB - UNLABELLED: 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.
U2 - 10.1158/0008-5472.CAN-22-2108
DO - 10.1158/0008-5472.CAN-22-2108
M3 - SCORING: Journal article
C2 - 36219398
VL - 82
SP - 4586
EP - 4603
JO - CANCER RES
JF - CANCER RES
SN - 0008-5472
IS - 24
ER -