Endothelial‐Mesenchymal Transition in Tumor Microenvironment Promotes Neuroendocrine Differentiation of Prostate Cancer

Neuroendocrine prostate cancer (NEPC) is a highly aggressive and treatment-resistant subtype of castration-resistant prostate cancer (CRPC) that often emerges during progression under androgen-receptor (AR) pathway inhibition. 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-mesenchymal 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-1β and TGF-β2, 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-macrophage colony-stimulating factor (GM-CSF) in EndoMTed HUVEC. Neutralization of GM-CSF signaling using mavrilimumab, a monoclonal antibody targeting the GM-CSF receptor alpha (CSF2RA), and siRNA-mediated CSF2RA knockdown both suppressed the neuroendocrine phenotype and STAT3 signaling of LNCaP cells. Conversely, GM-CSF stimulation alone reproduced these changes. Enzalutamide-treated LNCaP cells secreted IL-1β and TGF-β2, which in turn triggered EndoMT, suggesting a reciprocal loop. These findings indicate that anti-androgen therapy may inadvertently promote NEPC through a paracrine loop involving tumor-derived cytokines and endothelial GM-CSF secretion, highlighting EndoMT as a microenvironmental driver of treatment resistance.