RANK- and c-Met-mediated signal network promotes prostate cancer metastatic colonization

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dc.citation.firstpage311en_US
dc.citation.journalTitleEndocrine-Related Canceren_US
dc.citation.lastpage326en_US
dc.citation.volumeNumber21en_US
dc.contributor.authorChu, Gina Chia-Yien_US
dc.contributor.authorZhau, Haiyen E.en_US
dc.contributor.authorWang, Ruoxiangen_US
dc.contributor.authorRogatko, Andréen_US
dc.contributor.authorFeng, Xuen_US
dc.contributor.authorZayzafoon, Majden_US
dc.contributor.authorLiu, Youhuaen_US
dc.contributor.authorFarach-Carson, Mary C.en_US
dc.contributor.authorYou, Sungyongen_US
dc.contributor.authorKim, Jayoungen_US
dc.contributor.authorFreeman, Michael R.en_US
dc.contributor.authorChung, Leland W.K.en_US
dc.date.accessioned2014-10-09T15:38:24Zen_US
dc.date.available2014-10-09T15:38:24Zen_US
dc.date.issued2014en_US
dc.description.abstractProstate cancer (PCa) metastasis to bone is lethal and there is no adequate animal model to study the mechanisms underlying the metastatic process. Here we report that receptor activator of NF-κB ligand (RANKL) expressed by PCa cells consistently induced colonization or metastasis to bone in animal models. RANK-mediated signaling established a premetastatic niche through a feed forward loop, involving the induction of RANKL and c-Met, but repression of androgen receptor (AR) expression and AR signaling pathways. Site-directed mutagenesis and transcription factor deletion/interference assays identified common transcription factor complexes (TFs), c-Myc/Max and AP4, as critical regulatory nodes. RANKL-RANK signaling activated a number of master regulator TFs that control the epithelial-mesenchymal transition (EMT) (Twist1, Slug, Zeb1, Zeb2), stem cell properties (Sox2, Myc, Oct3/4 and Nanog), neuroendocrine differentiation (Sox 9, HIF-1α and FoxA2) and osteomimicry (c-Myc/Max, Sox2, Sox9, HIF1α and Runx2). Abrogating RANK or its downstream c-Myc/Max or c-Met signaling network, minimized or abolished skeletal metastasis in mice. RANKL-expressing LNCaP cells recruited and induced neighboring non-tumorigenic LNCaP cells to express RANKL, c-Met/activated c-Met, while downregulating AR expression. These initially non-tumorigenic cells, once retrieved from the tumors, acquired the potential to colonize and grow in bone. These findings identify a novel mechanism of tumor growth in bone that involves tumor cell reprogramming via RANK-RANKL signaling, as well as a form of signal amplification that mediates recruitment and stable transformation of non-metastatic cells.en_US
dc.identifier.citationChu, Gina Chia-Yi, Zhau, Haiyen E., Wang, Ruoxiang, et al.. "RANK- and c-Met-mediated signal network promotes prostate cancer metastatic colonization." <i>Endocrine-Related Cancer,</i> 21, (2014) Bioscientifica Ltd.: 311-326. http://dx.doi.org/10.1530/ERC-13-0548.en_US
dc.identifier.doihttp://dx.doi.org/10.1530/ERC-13-0548en_US
dc.identifier.urihttps://hdl.handle.net/1911/77501en_US
dc.language.isoengen_US
dc.publisherBioscientifica Ltd.en_US
dc.rightsThis work is licensed under a Creative Commons Attribution 3.0 Unported License.en_US
dc.rights.urihttps://creativecommons.org/licenses/by/3.0/en_US
dc.subject.keywordRANKLen_US
dc.subject.keywordRANKen_US
dc.subject.keywordc-Meten_US
dc.subject.keywordprostate canceren_US
dc.subject.keywordmetastasisen_US
dc.subject.keywordcancer dormancyen_US
dc.titleRANK- and c-Met-mediated signal network promotes prostate cancer metastatic colonizationen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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