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While lineage plasticity in cancer cells has been recognized as a key mechanism of resistance, the role of the tumor microenvironment in driving this transition remains unclear. Among its cellular components, vascular endothelial cells can undergo endothelial\u2010mesenchymal transition (EndoMT), a phenotypic shift associated with tumor progression and fibrosis. Here, we investigated whether EndoMT contributes to NEPC development. Human umbilical vein endothelial cells (HUVEC) were induced to undergo EndoMT using IL\u20101\u03b2 and TGF\u2010\u03b22, and are hereafter referred to as EndoMTed HUVEC. EndoMTed HUVEC promoted neuroendocrine features and functional changes in LNCaP cells. Transcriptome analysis revealed marked upregulation of granulocyte\u2010macrophage colony\u2010stimulating factor (GM\u2010CSF) in EndoMTed HUVEC. Neutralization of GM\u2010CSF signaling using mavrilimumab, a monoclonal antibody targeting the GM\u2010CSF receptor alpha (CSF2RA), and siRNA\u2010mediated CSF2RA knockdown both suppressed the neuroendocrine phenotype and STAT3 signaling of LNCaP cells. Conversely, GM\u2010CSF stimulation alone reproduced these changes. Enzalutamide\u2010treated LNCaP cells secreted IL\u20101\u03b2 and TGF\u2010\u03b22, which in turn triggered EndoMT, suggesting a reciprocal loop. These findings indicate that anti\u2010androgen therapy may inadvertently promote NEPC through a paracrine loop involving tumor\u2010derived cytokines and endothelial GM\u2010CSF secretion, highlighting EndoMT as a microenvironmental driver of treatment resistance.<\/jats:p>","DOI":"10.1111\/cas.70144","type":"journal-article","created":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T23:28:32Z","timestamp":1753399712000},"page":"2712-2722","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Endothelial\u2010Mesenchymal Transition in Tumor Microenvironment Promotes Neuroendocrine Differentiation of Prostate Cancer"],"prefix":"10.1111","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3690-2973","authenticated-orcid":false,"given":"Takumi","family":"Kageyama","sequence":"first","affiliation":[{"name":"Department of Nephro\u2010Urologic Surgery and Andrology Mie University Graduate School of Medicine  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