Neuroendocrine prostate cancer converges on a fetal pulmonary neuroendocrine-like program

Advanced prostate cancer can relapse as neuroendocrine prostate cancer (NEPC), a treatment-resistant, androgen receptor (AR)-independent state whose developmental identity remains unclear. We integrated single-cell, bulk, cistrome and spatial datasets from multiple cohorts and mapped malignant states to human fetal atlases. In the discovery cohort (35,696 tumor cells, 20 patients), NEPC cells were malignant and shared copy-number architecture with adenocarcinoma (chromosome-level r = 0.64). NEPC most closely matched a fetal, lineage-restricted neuroendocrine program, best supported as pulmonary neuroendocrine-like among alternatives tested (islet, chromaffin, sympathoblast), with consistent direction across three cohorts; the pulmonary-versus-islet distinction was method-sensitive and remains provisional. Stage and pseudotime analyses supported an ordered luminal-to-neuroendocrine sequence, with FOXA2/SOX2 early and ASCL1/NEUROD1/MYCN late across five datasets. A regulatory screen nominated a circuit centered on ASCL1 whose convergent enhancers overlapped fetal pulmonary neuroendocrine chromatin and showed FOXA1 binding in cell-line and xenograft models (87.0% versus 33.8%; P = 0.016). In one NEPC Visium section, the program localized to malignant territory defined by copy number (AUROC 0.85). Based on three NEPC patients with cross-cohort replication, these data support NEPC as an adenocarcinoma-related malignant state converging on a fetal pulmonary neuroendocrine-like program and nominate ASCL1-linked regulatory and surface targets.