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.