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Frizzled-8 integrates Wnt-11 and transforming growth factor-β signaling in prostate cancer

Author

Listed:
  • Virginia Murillo-Garzón

    (CIC bioGUNE)

  • Irantzu Gorroño-Etxebarria

    (CIC bioGUNE)

  • Malin Åkerfelt

    (University of Turku)

  • Mikael Christer Puustinen

    (Åbo Akademi University)

  • Lea Sistonen

    (Åbo Akademi University)

  • Matthias Nees

    (University of Turku)

  • James Carton

    (University of Turku)

  • Jonathan Waxman

    (Imperial College London)

  • Robert M. Kypta

    (CIC bioGUNE
    Imperial College London)

Abstract

Wnt-11 promotes cancer cell migration and invasion independently of β-catenin but the receptors involved remain unknown. Here, we provide evidence that FZD8 is a major Wnt-11 receptor in prostate cancer that integrates Wnt-11 and TGF-β signals to promote EMT. FZD8 mRNA is upregulated in multiple prostate cancer datasets and in metastatic cancer cell lines in vitro and in vivo. Analysis of patient samples reveals increased levels of FZD8 in cancer, correlating with Wnt-11. FZD8 co-localizes and co-immunoprecipitates with Wnt-11 and potentiates Wnt-11 activation of ATF2-dependent transcription. FZD8 silencing reduces prostate cancer cell migration, invasion, three-dimensional (3D) organotypic cell growth, expression of EMT-related genes, and TGF-β/Smad-dependent signaling. Mechanistically, FZD8 forms a TGF-β-regulated complex with TGF-β receptors that is mediated by the extracellular domains of FZD8 and TGFBR1. Targeting FZD8 may therefore inhibit aberrant activation of both Wnt and TGF-β signals in prostate cancer.

Suggested Citation

  • Virginia Murillo-Garzón & Irantzu Gorroño-Etxebarria & Malin Åkerfelt & Mikael Christer Puustinen & Lea Sistonen & Matthias Nees & James Carton & Jonathan Waxman & Robert M. Kypta, 2018. "Frizzled-8 integrates Wnt-11 and transforming growth factor-β signaling in prostate cancer," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04042-w
    DOI: 10.1038/s41467-018-04042-w
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