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

Alexandra Avgustinova, Marjan Iravani, David Robertson, Antony Fearns, Qiong Gao, Pamela Klingbeil, Andrew M Hanby, Valerie Speirs, Erik Sahai, Fernando Calvo, Clare M Isacke

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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 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.

Original languageEnglish
Article number10305
JournalNature Communications
Volume7
DOIs
Publication statusPublished - 18 Jan 2016

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fibroblasts
Fibroblasts
Tumors
tumors
Cells
Neoplasms
cancer
breast
Breast Neoplasms
Chemical activation
activation
phenotype
prognosis
promotion
metastasis
Extracellular Matrix
Crosstalk
crosstalk
progressions
Neoplasm Metastasis

Keywords

  • Animals
  • Breast Neoplasms
  • Female
  • Fibroblasts
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • NIH 3T3 Cells
  • Wnt Proteins
  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

Avgustinova, A., Iravani, M., Robertson, D., Fearns, A., Gao, Q., Klingbeil, P., ... Isacke, C. M. (2016). Tumour cell-derived Wnt7a recruits and activates fibroblasts to promote tumour aggressiveness. Nature Communications, 7, [10305]. https://doi.org/10.1038/ncomms10305

Tumour cell-derived Wnt7a recruits and activates fibroblasts to promote tumour aggressiveness. / Avgustinova, Alexandra; Iravani, Marjan; Robertson, David; Fearns, Antony; Gao, Qiong; Klingbeil, Pamela; Hanby, Andrew M; Speirs, Valerie; Sahai, Erik; Calvo, Fernando; Isacke, Clare M.

In: Nature Communications, Vol. 7, 10305, 18.01.2016.

Research output: Contribution to journalArticle

Avgustinova, A, Iravani, M, Robertson, D, Fearns, A, Gao, Q, Klingbeil, P, Hanby, AM, Speirs, V, Sahai, E, Calvo, F & Isacke, CM 2016, 'Tumour cell-derived Wnt7a recruits and activates fibroblasts to promote tumour aggressiveness', Nature Communications, vol. 7, 10305. https://doi.org/10.1038/ncomms10305
Avgustinova A, Iravani M, Robertson D, Fearns A, Gao Q, Klingbeil P et al. Tumour cell-derived Wnt7a recruits and activates fibroblasts to promote tumour aggressiveness. Nature Communications. 2016 Jan 18;7. 10305. https://doi.org/10.1038/ncomms10305
Avgustinova, Alexandra ; Iravani, Marjan ; Robertson, David ; Fearns, Antony ; Gao, Qiong ; Klingbeil, Pamela ; Hanby, Andrew M ; Speirs, Valerie ; Sahai, Erik ; Calvo, Fernando ; Isacke, Clare M. / Tumour cell-derived Wnt7a recruits and activates fibroblasts to promote tumour aggressiveness. In: Nature Communications. 2016 ; Vol. 7.
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title = "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 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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