Tumour cell-derived Wnt7a recruits and activates fibroblasts to promote tumour aggressiveness

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作者
Alexandra Avgustinova
Marjan Iravani
David Robertson
Antony Fearns
Qiong Gao
Pamela Klingbeil
Andrew M. Hanby
Valerie Speirs
Erik Sahai
Fernando Calvo
Clare M. Isacke
机构
[1] The Breast Cancer Now Toby Robins Research Centre,
[2] The Institute of Cancer Research,undefined
[3] Leeds Institute of Cancer and Pathology,undefined
[4] University of Leeds,undefined
[5] Tumour Cell Biology Laboratory,undefined
[6] Francis Crick Institute,undefined
[7] 44 Lincoln's Inn Fields,undefined
[8] Tumour Microenvironment Team,undefined
[9] The Institute of Cancer Research,undefined
[10] Present address: Institute for Research in Biomedicine Barcelona,undefined
[11] C/ Baldiri Reixac 10,undefined
[12] 08028 Barcelona,undefined
[13] Spain.,undefined
[14] Present address: Evotec AG,undefined
[15] Essener Bogen 7,undefined
[16] 22419 Hamburg,undefined
[17] Germany.,undefined
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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.
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