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

ABSTRACT: 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 TGF? 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.

SUBMITTER: Avgustinova A

PROVIDER: S-EPMC4735631 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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

Avgustinova Alexandra A Iravani Marjan M Robertson David D Fearns Antony A Gao Qiong Q Klingbeil Pamela P Hanby Andrew M AM Speirs Valerie V Sahai Erik E Calvo Fernando F Isacke Clare M CM

Nature communications 20160118

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, ...[more]

PMID: 26777421

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

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

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