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 and Eldad Zacksenhaus ()
Additional contact information
Philip E. D. Chung: University Health Network
Deena M. A. Gendoo: University of Birmingham
Ronak Ghanbari-Azarnier: University Health Network
Jeff C. Liu: University Health Network
Zhe Jiang: University Health Network
Jennifer Tsui: University Health Network
Dong-Yu Wang: University Health Network
Xiao Xiao: University Health Network
Bryan Li: University of Toronto
Adrian Dubuc: University of Toronto
David Shih: University of Toronto
Marc Remke: The Hospital for Sick Children
Ben Ho: The Hospital for Sick Children
Livia Garzia: The Hospital for Sick Children
Yaacov Ben-David: The Key laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences
Seok-Gu Kang: Yonsei University College of Medicine
Sidney Croul: Dalhousie University
Benjamin Haibe-Kains: University Health Network
Annie Huang: University of Toronto
Michael D. Taylor: University of Toronto
Eldad Zacksenhaus: University Health Network

Nature Communications, 2020, vol. 11, issue 1, 1-19

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15585-2

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