Frizzled-8 integrates Wnt-11 and transforminggrowth factor-βsignaling in prostate cancer

Virginia Murillo-Garzón, Irantzu Gorroño-Etxebarria, Malin Åkerfelt, Mikael Puustinen, Lea Sistonen, Matthias Nees, James Carton, Jonathan Waxman, Robert M. Kypta

Research output: Contribution to journalArticleScientificpeer-review

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Abstract

Wnt-11 promotes cancer cell migration and invasion independently of beta-catenin but the receptors involved remain unknown. Here, we provide evidence that FZD(8) is a major Wnt-11 receptor in prostate cancer that integrates Wnt-11 and TGF-beta signals to promote EMT. FZD(8) 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 FZD(8) in cancer, correlating with Wnt-11. FZD(8) co-localizes and co-immunoprecipitates with Wnt-11 and potentiates Wnt-11 activation of ATF2-dependent transcription. FZD(8) silencing reduces prostate cancer cell migration, invasion, three-dimensional (3D) organotypic cell growth, expression of EMT-related genes, and TGF-beta/Smad-dependent signaling. Mechanistically, FZD(8) forms a TGF-beta-regulated complex with TGF-beta receptors that is mediated by the extracellular domains of FZD(8) and TGFBR1. Targeting FZD(8) may therefore inhibit aberrant activation of both Wnt and TGF-beta signals in prostate cancer.
Original languageUndefined/Unknown
Pages (from-to)
Number of pages16
JournalNature Communications
Volume9
DOIs
Publication statusPublished - 2018
MoE publication typeA1 Journal article-refereed

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