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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, Vol. 82, No. 24, 16.12.2022, p. 4586-4603.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Borgenvik, A, Holmberg, KO, Bolin, S, Zhao, M, Savov, V, Rosén, G, Hutter, S, Garancher, A, Suryo Rahmanto, A, Bergström, T, Olsen, TK, Mainwaring, OJ, Sattanino, D, Verbaan, AD, Rusert, JM, Sundstrom, A, Ballester Bravo, M, Dang, Y, Wenz, AS, Richardson, S, Fotaki, G, Hill, RM, Dubuc, AM, Kalushkova, A, Remke, M, Cancer, M, Jernberg-Wiklund, H, Giraud, G, Chen, X, Taylor, MD, Sangfelt, O, Clifford, SC, Schüller, U, Wechsler-Reya, RJ, Weishaupt, H & Swartling, FJ 2022, 'Dormant SOX9-positive cells facilitate MYC-driven recurrence of medulloblastoma', CANCER RES, vol. 82, no. 24, pp. 4586-4603. https://doi.org/10.1158/0008-5472.CAN-22-2108

APA

Borgenvik, A., Holmberg, K. O., Bolin, S., Zhao, M., Savov, V., Rosén, G., Hutter, S., Garancher, A., Suryo Rahmanto, A., Bergström, T., Olsen, T. K., Mainwaring, O. J., Sattanino, D., Verbaan, A. D., Rusert, J. M., Sundstrom, A., Ballester Bravo, M., Dang, Y., Wenz, A. S., ... Swartling, F. J. (2022). Dormant SOX9-positive cells facilitate MYC-driven recurrence of medulloblastoma. CANCER RES, 82(24), 4586-4603. https://doi.org/10.1158/0008-5472.CAN-22-2108

Vancouver

Borgenvik A, Holmberg KO, Bolin S, Zhao M, Savov V, Rosén G et al. Dormant SOX9-positive cells facilitate MYC-driven recurrence of medulloblastoma. CANCER RES. 2022 Dec 16;82(24):4586-4603. https://doi.org/10.1158/0008-5472.CAN-22-2108

Bibtex

@article{668f1f9021df43699fcf88e18b4db7be,
title = "Dormant SOX9-positive cells facilitate MYC-driven recurrence of medulloblastoma",
abstract = "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.",
author = "Anna Borgenvik and Holmberg, {Karl O} and Sara Bolin and Miao Zhao and Vasil Savov and Gabriela Ros{\'e}n and Sonja Hutter and Alexandra Garancher and {Suryo Rahmanto}, Aldwin and Tobias Bergstr{\"o}m and Olsen, {Thale Kristin} and Mainwaring, {Oliver J} and Damiana Sattanino and Verbaan, {Annemieke D} and Rusert, {Jessica M} and Anders Sundstrom and {Ballester Bravo}, Mar and Yonglong Dang and Wenz, {Amelie S} and Stacey Richardson and Grammatiki Fotaki and Hill, {Rebecca M} and Dubuc, {Adrian M} and Antonia Kalushkova and Marc Remke and Matko Cancer and Helena Jernberg-Wiklund and G{\'e}raldine Giraud and Xingqi Chen and Taylor, {Michael D} and Olle Sangfelt and Clifford, {Steven C} and Ulrich Sch{\"u}ller and Wechsler-Reya, {Robert J} and Holger Weishaupt and Swartling, {Fredrik J}",
year = "2022",
month = dec,
day = "16",
doi = "10.1158/0008-5472.CAN-22-2108",
language = "English",
volume = "82",
pages = "4586--4603",
journal = "CANCER RES",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "24",

}

RIS

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 -