Modeling germline mutations in pineoblastoma uncovers lysosome disruption-based therapy
Research output: Contribution to journal › Article › peer-review
Colleges, School and Institutes
- The University of Toronto, Toronto, Canada
- UNIVERSITY HEALTH NETWORK
- State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550025, China.
- Developmental & Stem Cell Biology Program
- McGill Center for Bioinformatics, McGill University, Montreal, Quebec, Canada
- Yonsei University College of Medicine
- Dalhousie University
- Vector Institute, Toronto, Ontario, Canada.
- The Arthur and Sonia Labatt Brain Tumour Research Centre and Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario, Canada.
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.
|Number of pages||19|
|Publication status||Published - 14 Apr 2020|