LHX2 drives neuroendocrine transformation in TP53/RB1-deficient prostate cancer

Neuroendocrine prostate cancer (NEPC) is an aggressive subtype that progresses after androgen deprivation therapy (ADT) resistance and has extremely poor prognosis. Its underlying regulatory mechanisms remain incompletely understood. Through analyses of cell lines, organoids, transgenic mouse models, and clinical samples, this study systematically revealed the core role and regulatory network of LIM homeobox transcription factor 2 (LHX2) in NEPC occurrence and development. In the genetic context of TP53/RB1 deficiency, LHX2 is activated and induces prostate cancer cell transdifferentiation into a neuroendocrine (NE) phenotype. LHX2 and FOXA2 exhibit a mutually exclusive expression pattern, forming two NEPC subpopulations (FOXA2high and LHX2high) that synergistically maintain NE features. Analysis of clinical samples demonstrated that LHX2 expression was closely associated with NEPC progression and ADT resistance. The LHX2-001 transcript containing the LIM domain was found to be the key subtype driving NE transformation, and was found to functionally depend on the transcriptional coactivator CEBPB and to collectively regulate the expression of NE genes. ACTIVIN, identified as a signal specific to the LHX2high subpopulation, played a major role in enhancing tumor stemness, and its key receptor ACVR2B was transcriptionally regulated by LHX2. Targeted blocking of Activin A (garetosmab) effectively inhibited the progression of LHX2-overexpressing tumors. Our findings clarified the molecular mechanism through which specific LHX2 transcripts drive NEPC, revealed the subtype heterogeneity of NEPC, and may provide a new theoretical basis and potential targets for NEPC diagnosis and targeted therapy.