Prostate cancer (PCa) is highly sensitive to hormone therapy because androgens are essential for prostate cancer cell growth. However, with the nearly invariable progression of this disease to androgen independence (AI), endocrine therapy ultimately fails to control PCa in most patients. AI acquisition may involve neuroendocrine (NE) transdifferentiation, but there is little knowledge about this process, which is presently controversial. In this study, we investigated this question in a novel model of human androgen-dependent LNCaP cells cultured for long periods in hormone-deprived conditions. Strikingly, characterization of the NE phenotype by transcriptomic, metabolomic and other statistically integrated analyses showed how hormone-deprived LNCaP cells could transdifferentiate to a non-malignant NE phenotype. Notably, conditioned media from NE-like cells affected LNCaP cell proliferation. Predictive in silico models illustrated how after an initial period, when LNCaP cell survival was compromised by an arising population of NE-like cells, a sudden trend reversal occurred in which the NE-like cells functioned to sustain the remaining androgen-dependent LNCaP cells. Our findings provide direct biological and molecular support for the concept that NE transdifferentiation in PCa cell populations influences the progression to androgen independence.