YAP1/TAZ drives ependymoma-like tumour formation in mice

Noreen Eder, Federico Roncaroli, Marie-Charlotte Domart, Stuart Horswell, Felipe Andreiuolo, Helen R. Flynn, Andre T. Lopes, Suzanne Claxton, John-Paul Kilday, Lucy Collinson, Jun-Hao Mao, Torsten Pietsch, Barry Thompson, Ambrosius P. Snijders and Sila K. Ultanir ()
Additional contact information
Noreen Eder: Kinases and Brain Development Laboratory, The Francis Crick Institute
Federico Roncaroli: Manchester Centre for Clinical Neuroscience, Salford Royal NHS Foundation Trust, Salford and Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biology, University of Manchester
Marie-Charlotte Domart: Electron Microscopy Platform, The Francis Crick Institute
Stuart Horswell: Bioinformatics and Biostatistics Platform, The Francis Crick Institute
Felipe Andreiuolo: Institute of Neuropathology, DGNN Brain Tumour Reference Center, University of Bonn
Helen R. Flynn: Protein Analysis and Proteomics Platform, The Francis Crick Institute
Andre T. Lopes: Kinases and Brain Development Laboratory, The Francis Crick Institute
Suzanne Claxton: Kinases and Brain Development Laboratory, The Francis Crick Institute
John-Paul Kilday: Centre for Paediatric, Teenage and Young Adult Cancer, Faculty of Biology, Medicine and Health, University of Manchester
Lucy Collinson: Electron Microscopy Platform, The Francis Crick Institute
Jun-Hao Mao: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School
Torsten Pietsch: Institute of Neuropathology, DGNN Brain Tumour Reference Center, University of Bonn
Barry Thompson: Epithelial Biology Laboratory, The Francis Crick Institute
Ambrosius P. Snijders: Protein Analysis and Proteomics Platform, The Francis Crick Institute
Sila K. Ultanir: Kinases and Brain Development Laboratory, The Francis Crick Institute

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract YAP1 gene fusions have been observed in a subset of paediatric ependymomas. Here we show that, ectopic expression of active nuclear YAP1 (nlsYAP5SA) in ventricular zone neural progenitor cells using conditionally-induced NEX/NeuroD6-Cre is sufficient to drive brain tumour formation in mice. Neuronal differentiation is inhibited in the hippocampus. Deletion of YAP1’s negative regulators LATS1 and LATS2 kinases in NEX-Cre lineage in double conditional knockout mice also generates similar tumours, which are rescued by deletion of YAP1 and its paralog TAZ. YAP1/TAZ-induced mouse tumours display molecular and ultrastructural characteristics of human ependymoma. RNA sequencing and quantitative proteomics of mouse tumours demonstrate similarities to YAP1-fusion induced supratentorial ependymoma. Finally, we find that transcriptional cofactor HOPX is upregulated in mouse models and in human YAP1-fusion induced ependymoma, supporting their similarity. Our results show that uncontrolled YAP1/TAZ activity in neuronal precursor cells leads to ependymoma-like tumours in mice.

Date: 2020
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DOI: 10.1038/s41467-020-16167-y

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