HOXD11 drives NMDAR signaling activation and the neuroendocrine transition in prostate cancer epithelium

Prostate cancer frequently develops resistance to androgen deprivation
therapy (ADT), with adenocarcinoma-neuroendocrine prostate cancer (NEPC)
lineage plasticity representing a critical yet mechanistically unclear
driver of therapeutic failure. Here, we employ single-cell transcriptomic
analysis of 29,436 cells from transgenic adenocarcinoma of mouse prostate
(TRAMP), recapitulating the full clinical progression of human prostate
cancer-NEPC evolution, to dissect the molecular dynamics underlying
lineage transition. We identify Hoxd11 as a key transcriptional driver of
adenocarcinoma-NEPC plasticity, with its expression and regulatory
activity markedly upregulated during early NEPC transformation. Genetic
suppression of Hoxd11 reversed lineage plasticity and delayed ADT-induced
neuroendocrine differentiation. Mechanistically, HOXD11 directly activates
the NMDAR signaling pathway (via GRIN1/GRIN3A), which is hyperactivated in
NEPC and correlates with poor prognosis. Pharmacological inhibition of
NMDAR using the clinically available antagonist memantine significantly
suppressed tumor growth in murine models. These findings position the
HOXD11-NMDAR axis as a druggable pathway in NEPC, with memantine
repurposing offering near-term therapeutic potential.