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The interplay of the tumor microenvironment, encompassing secreted soluble factors, plays a crucial role in facilitating liver metastasis. In this study, the role is elucidated of the neural growth factor\u2010inducible gene (VGF), a secreted neuropeptide precursor, in G\u03b1q mutant UM. Employing a multiomics approach, encompassing transcriptomic and secretomic analyses, the intricate involvement of VGF in UM progression is unveiled. VGF is upregulated in G\u03b1q mutant UM cells and associated with poor prognosis of UM patients. Targeting VGF significantly suppressed the growth of UM in vitro and in vivo. Further evidence shows that VGF is regulated by G\u03b1q through MAPK\/CREB pathway. Mechanistically, CREB modulates VGF expression by directly binding to consensus DNA response elements in the promoters of the VGF gene. Combined inhibition of G\u03b1q and MEK remarkably reduces tumor burden in the UM xenograft model. Notably, VGF triggers liver metastatic colonization of UM and activates the fibrosis of hepatic stellate cells (HSCs), creating a favorable microenvironment, through an autocrine and paracrine loop. Furthermore, VGF directly binds to TGFBR2 and regulates TGF\u2010\u03b2\u2010SMAD signaling pathway, thereby regulating genes associated with endothelial\u2010mesenchymal transition (EMT) to promote metastasis. Taken together, these findings identify VGF as a pivotal driver in the progression and metastasis of G\u03b1q mutant UM and confers a promising therapeutic target and strategy for UM patients.<\/jats:p>","DOI":"10.1002\/advs.202407967","type":"journal-article","created":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T10:44:54Z","timestamp":1729248294000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Neuropeptide Precursor VGF Promotes Liver Metastatic Colonization of G\u03b1q Mutant Uveal Melanoma by Facilitating Tumor Microenvironment via Paracrine Loops"],"prefix":"10.1002","volume":"11","author":[{"given":"Shumin","family":"Ouyang","sequence":"first","affiliation":[{"name":"National\u2010Local Joint Engineering Laboratory of Druggability and New Drug Evaluation Guangdong Key Laboratory of Chiral Molecule and Drug Discovery School of Pharmaceutical Sciences Sun Yat\u2010sen University  Guangzhou 510006 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