Modeling germline mutations in pineoblastoma uncovers lysosome disruption-based therapy

Philip E.D. Chung; Deena M.A. Gendoo; Ronak Ghanbari-Azarnier; Jeff C. Liu; Zhe Jiang; Jennifer Tsui; Dong Yu Wang; Xiao Xiao; Bryan Li; Adrian Dubuc; David Shih; Marc Remke; Ben Ho; Livia Garzia; Yaacov Ben-David; Seok Gu Kang; Sidney Croul; Benjamin Haibe-Kains; Annie Huang; Michael D. Taylor; Eldad Zacksenhaus

doi:10.1038/s41467-020-15585-2

Modeling germline mutations in pineoblastoma uncovers lysosome disruption-based therapy

Philip E.D. Chung, Deena M.A. Gendoo, Ronak Ghanbari-Azarnier, Jeff C. Liu, Zhe Jiang, Jennifer Tsui, Dong Yu Wang, Xiao Xiao, Bryan Li, Adrian Dubuc, David Shih, Marc Remke, Ben Ho, Livia Garzia, Yaacov Ben-David, Seok Gu Kang, Sidney Croul, Benjamin Haibe-Kains, Annie Huang, Michael D. TaylorEldad Zacksenhaus

Department of Neurosurgery

Research output: Contribution to journal › Article › peer-review

16 Citations (Scopus)

Abstract

Pineoblastoma is a rare pediatric cancer induced by germline mutations in the tumor suppressors RB1 or DICER1. Presence of leptomeningeal metastases is indicative of poor prognosis. Here we report that inactivation of Rb plus p53 via a WAP-Cre transgene, commonly used to target the mammary gland during pregnancy, induces metastatic pineoblastoma resembling the human disease with 100% penetrance. A stabilizing mutation rather than deletion of p53 accelerates metastatic dissemination. Deletion of Dicer1 plus p53 via WAP-Cre also predisposes to pineoblastoma, albeit with lower penetrance. In silico analysis predicts tricyclic antidepressants such as nortriptyline as potential therapeutics for both pineoblastoma models. Nortriptyline disrupts the lysosome, leading to accumulation of non-functional autophagosome, cathepsin B release and pineoblastoma cell death. Nortriptyline further synergizes with the antineoplastic drug gemcitabine to effectively suppress pineoblastoma in our preclinical models, offering new modality for this lethal childhood malignancy.

Original language	English
Article number	1825
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-15585-2
Publication status	Published - 2020 Dec 1

Bibliographical note

Funding Information:
We thank Dr. Michael Salter for access to his freezing microtome. This research was funded by grants from the Canadian Institute of Health Research (CIHR) to E.Z. and from Terry Fox Research Institute Program Grant to M.D.T. and E.Z.

Publisher Copyright:
© 2020, The Author(s).

All Science Journal Classification (ASJC) codes

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/s41467-020-15585-2

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Chung, P. E. D., Gendoo, D. M. A., Ghanbari-Azarnier, R., Liu, J. C., Jiang, Z., Tsui, J., Wang, D. Y., Xiao, X., Li, B., Dubuc, A., Shih, D., Remke, M., Ho, B., Garzia, L., Ben-David, Y., Kang, S. G., Croul, S., Haibe-Kains, B., Huang, A., ... Zacksenhaus, E. (2020). Modeling germline mutations in pineoblastoma uncovers lysosome disruption-based therapy. Nature communications, 11(1), Article 1825. https://doi.org/10.1038/s41467-020-15585-2

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title = "Modeling germline mutations in pineoblastoma uncovers lysosome disruption-based therapy",

abstract = "Pineoblastoma is a rare pediatric cancer induced by germline mutations in the tumor suppressors RB1 or DICER1. Presence of leptomeningeal metastases is indicative of poor prognosis. Here we report that inactivation of Rb plus p53 via a WAP-Cre transgene, commonly used to target the mammary gland during pregnancy, induces metastatic pineoblastoma resembling the human disease with 100% penetrance. A stabilizing mutation rather than deletion of p53 accelerates metastatic dissemination. Deletion of Dicer1 plus p53 via WAP-Cre also predisposes to pineoblastoma, albeit with lower penetrance. In silico analysis predicts tricyclic antidepressants such as nortriptyline as potential therapeutics for both pineoblastoma models. Nortriptyline disrupts the lysosome, leading to accumulation of non-functional autophagosome, cathepsin B release and pineoblastoma cell death. Nortriptyline further synergizes with the antineoplastic drug gemcitabine to effectively suppress pineoblastoma in our preclinical models, offering new modality for this lethal childhood malignancy.",

author = "Chung, {Philip E.D.} and Gendoo, {Deena M.A.} and Ronak Ghanbari-Azarnier and Liu, {Jeff C.} and Zhe Jiang and Jennifer Tsui and Wang, {Dong Yu} and Xiao Xiao and Bryan Li and Adrian Dubuc and David Shih and Marc Remke and Ben Ho and Livia Garzia and Yaacov Ben-David and Kang, {Seok Gu} and Sidney Croul and Benjamin Haibe-Kains and Annie Huang and Taylor, {Michael D.} and Eldad Zacksenhaus",

note = "Funding Information: We thank Dr. Michael Salter for access to his freezing microtome. This research was funded by grants from the Canadian Institute of Health Research (CIHR) to E.Z. and from Terry Fox Research Institute Program Grant to M.D.T. and E.Z. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

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Chung, PED, Gendoo, DMA, Ghanbari-Azarnier, R, Liu, JC, Jiang, Z, Tsui, J, Wang, DY, Xiao, X, Li, B, Dubuc, A, Shih, D, Remke, M, Ho, B, Garzia, L, Ben-David, Y, Kang, SG, Croul, S, Haibe-Kains, B, Huang, A, Taylor, MD & Zacksenhaus, E 2020, 'Modeling germline mutations in pineoblastoma uncovers lysosome disruption-based therapy', Nature communications, vol. 11, no. 1, 1825. https://doi.org/10.1038/s41467-020-15585-2

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AU - Chung, Philip E.D.

AU - Gendoo, Deena M.A.

AU - Ghanbari-Azarnier, Ronak

AU - Liu, Jeff C.

AU - Jiang, Zhe

AU - Tsui, Jennifer

AU - Wang, Dong Yu

AU - Xiao, Xiao

AU - Li, Bryan

AU - Dubuc, Adrian

AU - Shih, David

AU - Remke, Marc

AU - Ho, Ben

AU - Garzia, Livia

AU - Ben-David, Yaacov

AU - Kang, Seok Gu

AU - Croul, Sidney

AU - Haibe-Kains, Benjamin

AU - Huang, Annie

AU - Taylor, Michael D.

AU - Zacksenhaus, Eldad

N1 - Funding Information: We thank Dr. Michael Salter for access to his freezing microtome. This research was funded by grants from the Canadian Institute of Health Research (CIHR) to E.Z. and from Terry Fox Research Institute Program Grant to M.D.T. and E.Z. Publisher Copyright: © 2020, The Author(s).

PY - 2020/12/1

Y1 - 2020/12/1

N2 - Pineoblastoma is a rare pediatric cancer induced by germline mutations in the tumor suppressors RB1 or DICER1. Presence of leptomeningeal metastases is indicative of poor prognosis. Here we report that inactivation of Rb plus p53 via a WAP-Cre transgene, commonly used to target the mammary gland during pregnancy, induces metastatic pineoblastoma resembling the human disease with 100% penetrance. A stabilizing mutation rather than deletion of p53 accelerates metastatic dissemination. Deletion of Dicer1 plus p53 via WAP-Cre also predisposes to pineoblastoma, albeit with lower penetrance. In silico analysis predicts tricyclic antidepressants such as nortriptyline as potential therapeutics for both pineoblastoma models. Nortriptyline disrupts the lysosome, leading to accumulation of non-functional autophagosome, cathepsin B release and pineoblastoma cell death. Nortriptyline further synergizes with the antineoplastic drug gemcitabine to effectively suppress pineoblastoma in our preclinical models, offering new modality for this lethal childhood malignancy.

AB - Pineoblastoma is a rare pediatric cancer induced by germline mutations in the tumor suppressors RB1 or DICER1. Presence of leptomeningeal metastases is indicative of poor prognosis. Here we report that inactivation of Rb plus p53 via a WAP-Cre transgene, commonly used to target the mammary gland during pregnancy, induces metastatic pineoblastoma resembling the human disease with 100% penetrance. A stabilizing mutation rather than deletion of p53 accelerates metastatic dissemination. Deletion of Dicer1 plus p53 via WAP-Cre also predisposes to pineoblastoma, albeit with lower penetrance. In silico analysis predicts tricyclic antidepressants such as nortriptyline as potential therapeutics for both pineoblastoma models. Nortriptyline disrupts the lysosome, leading to accumulation of non-functional autophagosome, cathepsin B release and pineoblastoma cell death. Nortriptyline further synergizes with the antineoplastic drug gemcitabine to effectively suppress pineoblastoma in our preclinical models, offering new modality for this lethal childhood malignancy.

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Modeling germline mutations in pineoblastoma uncovers lysosome disruption-based therapy

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

UN SDGs

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