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Modeling Germline Mutations in Pineoblastoma Uncovers Lysosome Disruption-Based Therapy

Authors
 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 
Citation
 NATURE COMMUNICATIONS, Vol.11(1) : 1825, 2020-04 
Journal Title
 NATURE COMMUNICATIONS 
Issue Date
2020-04
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.
Files in This Item:
T202001440.pdf Download
DOI
10.1038/s41467-020-15585-2
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Neurosurgery (신경외과학교실) > 1. Journal Papers
Yonsei Authors
Kang, Seok Gu(강석구) ORCID logo https://orcid.org/0000-0001-5676-2037
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/176153
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