Modeling germline mutations in pineoblastoma uncovers lysosome disruption-based therapy

Research output: Contribution to journalArticlepeer-review

Authors

  • Philip E D Chung
  • 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

Colleges, School and Institutes

External organisations

  • 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.

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.

Details

Original languageEnglish
Article number1825
Number of pages19
JournalNature Communications
Volume11
Issue number1
Publication statusPublished - 14 Apr 2020