摘要：SummaryNeuroendocrine prostate cancer (NEPC) is a lethal prostate cancer subtype arising as a consequence of more potent androgen receptor (AR) targeting in castration-resistant prostate cancer (CRPC). Its molecular pathogenesis remains elusive. Here, we report that the Wnt secretion mediator Wntless (WLS) is a major driver of NEPC and aggressive tumor growthin vitroandin vivo. Mechanistic studies showed that WLS is a transcriptional target suppressed by AR that activates the ROR2/PKCδ/ERK signaling pathway to support the neuroendocrine (NE) traits and proliferative capacity of NEPC cells. Analysis of clinical samples and datasets revealed that WLS was highly expressed in CRPC and NEPC tumors. Finally, treatment with the Wnt secretion inhibitor LGK974 restricted NE prostate tumor xenograft growth in mice. These findings collectively characterize the contribution of WLS to NEPC pathogenesis and suggest that WLS is a potential therapeutic target in NEPC.Graphical AbstractDisplay OmittedHighlights•WLS is highly expressed in neuroendocrine prostate cancer clinical samples•WLS is a transcriptional target suppressed by androgen receptor•WLS drives neuroendocrine prostate cancer through the ROR2/PKCδ/ERK pathway•Wnt secretion inhibitor treatment limits neuroendocrine prostate tumor growth in miceBiological Sciences; Cell Biology; Cancer; Transcriptomics
