| Tumour cell-derived Wnt7a recruits and activates fibroblasts to promote tumour aggressiveness | | Tumour cell-derived Wnt7a recruits and activates fibroblasts to promote tumour aggressiveness | Avgustinova A, Iravani M, Robertson D, Fearns A, Gao Q, Klingbeil P, Hanby AM, Speirs V, Sahai E, Calvo F, and Isacke CM | 2016-01-17T23:00:00Z | <p style="text-align:justify;"><strong class="ms-rteThemeFontFace-1 ms-rteFontSize-2">Abstract</strong></p><p style="text-align:justify;"><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#222222;letter-spacing:0.17000000178813934px;background-color:#ffffff;">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 </span><em class="ms-rteThemeFontFace-1 ms-rteFontSize-2">in vivo</em><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#222222;letter-spacing:0.17000000178813934px;background-color:#ffffff;"> 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 </span><em class="ms-rteThemeFontFace-1 ms-rteFontSize-2">in vitro</em><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#222222;letter-spacing:0.17000000178813934px;background-color:#ffffff;"> and </span><em class="ms-rteThemeFontFace-1 ms-rteFontSize-2">in vivo</em><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#222222;letter-spacing:0.17000000178813934px;background-color:#ffffff;"> 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.</span><br></p> | <p><a href="https://www.nature.com/articles/ncomms10305">Nature CommunicationsJan 18; 7:10305.</a><br></p> | 185 | | |
