Norrin/Frizzled4 signalling in the preneoplastic niche blocks medulloblastoma initiation.
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 thePtch+/-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.
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada.
Erin A
EA
Bassett
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada.|Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada.
Nicholas
N
Tokarew
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada.
Ema A
EA
Allemano
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada.
Chantal
C
Mazerolle
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada.
Katy
K
Morin
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada.
Alan J
AJ
Mears
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada.
Brian
B
McNeill
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada.|Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada.
Randy
R
Ringuette
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada.|Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada.
Charles
C
Campbell
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada.
Sheila
S
Smiley
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.|Donald K. Johnson Eye Institute, Krembil Research Institute, University Health Network, Toronto, Canada.
Neno T
NT
Pokrajac
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.
Adrian M
AM
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.|Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Canada.|Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Canada.
Vijay
V
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.
Paul A
PA
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
M
Remke
Genetics and Development Division, Krembil Research Institute, University Health Network, Toronto, Canada.|Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Canada.
Philippe P
PP
Monnier
Department of Ophthalmology, Lexicon Pharmaceuticals Inc., The Woodlands, United States.
David
D
Potter
Department of Ophthalmology, Lexicon Pharmaceuticals Inc., The Woodlands, United States.
Kim
K
Paes
Department of Ophthalmology, Lexicon Pharmaceuticals Inc., The Woodlands, United States.
Laura L
LL
Kirkpatrick
Department of Ophthalmology, Lexicon Pharmaceuticals Inc., The Woodlands, United States.
Kenneth J
KJ
Coker
Department of Ophthalmology, Lexicon Pharmaceuticals Inc., The Woodlands, United States.
Dennis S
DS
Rice
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada.|Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada.
Carol
C
Perez-Iratxeta
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.
Michael D
MD
Taylor
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.
Valerie A
0000-0003-3721-9017
VA
Wallace
D000818:Animals; D063646:Carcinogenesis; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000378:metabolism*; D051157:Frizzled Receptors / Q000378:metabolism*; D005786:Gene Expression Regulation; D008527:Medulloblastoma / Q000503:physiopathology*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D015398:Signal Transduction
D005136:Eye Proteins; D051157:Frizzled Receptors; C498581:Fzd4 protein, mouse; C489916:Ndph protein, mouse; D009419:Nerve Tissue Proteins
Frizzled4; Hedgehog; Medulloblastoma; Norrin; Patched; cancer biology; developmental biology; human; mouse; stem cells; stroma