Stromal fibroblast recruitment to tumours and activation to a cancer-associated fibroblast (CAF) phenotype has been implicated in promoting primary tumour growth and progression to metastatic disease. However, the mechanisms underlying the tumour:fibroblast crosstalk that drive the intertumoural stromal heterogeneity remain poorly understood. Using in vivo models we identify Wnt7a as a key factor secreted exclusively by aggressive breast tumour cells, which induces CAF conversion. Functionally, this results in extracellular matrix remodelling to create a permissive environment for tumour cell invasion and promotion of distant metastasis. Mechanistically, Wnt7a-mediated fibroblast activation is not dependent on classical Wnt signalling. Instead, we demonstrate that Wnt7a potentiates TGFβ receptor signalling both in 3D in vitro and in vivo models, thus highlighting the interaction between two of the key signalling pathways in development and disease. Importantly, in clinical breast cancer cohorts, tumour cell Wnt7a expression correlates with a desmoplastic, poor-prognosis stroma and poor patient outcome.
Bibliographical noteThis work was funded by Breakthrough Breast Cancer (recently merged with Breast Cancer Campaign forming Breast Cancer Now; C.M.I.), Cancer Research UK (A.A., E.S. and CMI) and Breast Cancer Campaign (V.S. and A.H.). F.C. is currently funded by The Institute of Cancer Research and Worldwide Cancer Research. We acknowledge NHS funding to the NIHR Biomedical Research Centre at The Royal Marsden and the ICR. We thank the Breakthrough Histopathology Facility, Cambridge Genomic Services for the gene expression analysis, Balazs Gyorffy for providing the clinical breast cancer outcome data, Antoinette van Weverwijk for help with the in vivo assays, Fredrik Wallberg for help with the FACSorting, Andrea Morandi for help with the TMA analysis, Patricia Salinas for the Wnt7a cDNA construct and helpful discussions and Lorenzo Melchor for the pDEST/pHIV-H2BmRFP-rfa_verB Gateway cloning vector.
- Breast Neoplasms
- Gene Expression Regulation, Neoplastic
- Mice, Inbred BALB C
- NIH 3T3 Cells
- Wnt Proteins
- Journal Article
- Research Support, Non-U.S. Gov't
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- School of Medicine, Medical Sciences & Nutrition, Molecular and Cellular Function
- School of Medicine, Medical Sciences & Nutrition, Medical Sciences - Chair in Molecular Oncology
- School of Medicine, Medical Sciences & Nutrition, Institute of Medical Sciences
- School of Medicine, Medical Sciences & Nutrition, Aberdeen Cancer Centre