10779/crick.12588581.v1 Alexandra Avgustinova Alexandra Avgustinova Marjan Iravani Marjan Iravani David Robertson David Robertson Antony Fearns Antony Fearns Qiong Gao Qiong Gao Pamela Klingbeil Pamela Klingbeil Andrew M Hanby Andrew M Hanby Valerie Speirs Valerie Speirs Erik Sahai Erik Sahai Fernando Calvo Fernando Calvo Clare M Isacke Clare M Isacke Tumour cell-derived Wnt7a recruits and activates fibroblasts to promote tumour aggressiveness The Francis Crick Institute 2020 Animals Breast Neoplasms Female Fibroblasts Gene Expression Regulation, Neoplastic Humans Mice Mice, Inbred BALB C NIH 3T3 Cells Wnt Proteins Sahai FC001144 2020-07-01 11:44:31 Journal contribution https://crick.figshare.com/articles/journal_contribution/Tumour_cell-derived_Wnt7a_recruits_and_activates_fibroblasts_to_promote_tumour_aggressiveness/12588581 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.