eLife (Nov 2016)
Norrin/Frizzled4 signalling in the preneoplastic niche blocks medulloblastoma initiation
- Erin A Bassett,
- Nicholas Tokarew,
- Ema A Allemano,
- Chantal Mazerolle,
- Katy Morin,
- Alan J Mears,
- Brian McNeill,
- Randy Ringuette,
- Charles Campbell,
- Sheila Smiley,
- Neno T Pokrajac,
- Adrian M Dubuc,
- Vijay Ramaswamy,
- Paul A Northcott,
- Marc Remke,
- Philippe P Monnier,
- David Potter,
- Kim Paes,
- Laura L Kirkpatrick,
- Kenneth J Coker,
- Dennis S Rice,
- Carol Perez-Iratxeta,
- Michael D Taylor,
- Valerie A Wallace
Affiliations
- Erin A Bassett
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada
- Nicholas Tokarew
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada
- Ema A Allemano
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada
- Chantal Mazerolle
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada
- Katy Morin
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada
- Alan J Mears
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada
- Brian McNeill
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada
- Randy Ringuette
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada
- Charles Campbell
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada
- Sheila Smiley
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada
- Neno T Pokrajac
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada; Donald K. Johnson Eye Institute, Krembil Research Institute, University Health Network, Toronto, Canada
- Adrian M Dubuc
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada; Developmental and Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, Canada
- Vijay Ramaswamy
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada; Developmental and Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, Canada; Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Canada; Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Canada
- Paul A Northcott
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada; Developmental and Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, Canada
- Marc Remke
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada; Developmental and Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, Canada
- Philippe P Monnier
- Genetics and Development Division, Krembil Research Institute, University Health Network, Toronto, Canada; Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Canada
- David Potter
- Department of Ophthalmology, Lexicon Pharmaceuticals Inc., The Woodlands, United States
- Kim Paes
- Department of Ophthalmology, Lexicon Pharmaceuticals Inc., The Woodlands, United States
- Laura L Kirkpatrick
- Department of Ophthalmology, Lexicon Pharmaceuticals Inc., The Woodlands, United States
- Kenneth J Coker
- Department of Ophthalmology, Lexicon Pharmaceuticals Inc., The Woodlands, United States
- Dennis S Rice
- Department of Ophthalmology, Lexicon Pharmaceuticals Inc., The Woodlands, United States
- Carol Perez-Iratxeta
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada
- Michael D Taylor
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada; Developmental and Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, Canada; Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Canada
- Valerie A Wallace
- ORCiD
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada; Donald K. Johnson Eye Institute, Krembil Research Institute, University Health Network, Toronto, Canada; Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Canada
- DOI
- https://doi.org/10.7554/eLife.16764
- Journal volume & issue
-
Vol. 5
Abstract
The tumor microenvironment is a critical modulator of carcinogenesis; however, in many tumor types, the influence of the stroma during preneoplastic stages is unknown. Here we explored the relationship between pre-tumor cells and their surrounding stroma in malignant progression of the cerebellar tumor medulloblastoma (MB). We show that activation of the vascular regulatory signalling axis mediated by Norrin (an atypical Wnt)/Frizzled4 (Fzd4) inhibits MB initiation in the Ptch+/− mouse model. Loss of Norrin/Fzd4-mediated signalling in endothelial cells, either genetically or by short-term blockade, increases the frequency of pre-tumor lesions and creates a tumor-permissive microenvironment at the earliest, preneoplastic stages of MB. This pro-tumor stroma, characterized by angiogenic remodelling, is associated with an accelerated transition from preneoplasia to malignancy. These data expose a stromal component that regulates the earliest stages of tumorigenesis in the cerebellum, and a novel role for the Norrin/Fzd4 axis as an endogenous anti-tumor signal in the preneoplastic niche.
Keywords