Abstract
Neuroendocrine prostate cancer (NEPC) is thought to arise as prostate adenocarcinoma cells transdifferentiate into neuroendocrine (NE) cells to escape potent anti-androgen therapies however, the exact molecular events accompanying NE transdifferentiation and their plasticity remain poorly defined. Cell fate regulator ASCL1/hASH1’s expression was markedly induced in androgen deprived (AD) LNCaP cells and prominent nuclear localisation accompanied acquisition of the NE-like morphology and expression of NE markers (NSE). By contrast, androgen-insensitive PC3 and DU145 cells displayed clear nuclear hASH1 localisation under control conditions that was unchanged by AD, suggesting AR signalling negatively regulated hASH1 expression and localisation. Synthetic androgen (R1881) prevented NE transdifferentiation of AD LNCaP cells and markedly suppressed expression of key regulators of lineage commitment and neurogenesis (REST and ASCL1/hASH1). Post-AD, NE LNCaP cells rapidly lost NE-like morphology following R1881 treatment, yet ASCL1/hASH1 expression was resistant to R1881 treatment and hASH1 nuclear localisation remained evident in apparently dedifferentiated LNCaP cells. Consequently, NE cells may not fully revert to an epithelial state and retain key NE-like features, suggesting a “hybrid” phenotype. This could fuel greater NE transdifferentiation, therapeutic resistance and NEPC evolution upon subsequent androgen deprivation. Such knowledge could facilitate CRPC tumour stratification and identify targets for more effective NEPC management.
Highlights
Neuroendocrine prostate cancer (NEPC) is thought to arise as prostate adenocarcinoma cells transdifferentiate into neuroendocrine (NE) cells to escape potent anti-androgen therapies the exact molecular events accompanying NE transdifferentiation and their plasticity remain poorly defined
The molecular mechanisms involved in transdifferentiation of prostate adenocarcinoma were investigated by culturing androgen sensitive, LNCaP cells and androgen-insensitive, DU145 and PC314 cells (Fig. 1A,B) in phenol-red free medium containing charcoal stripped serum to remove androgens and mimic androgen deprivation (AD)[15,16]
MMP9 expression was increased in an incremental fashion by sequential rounds of androgen deprived (AD) in LNCaP cells (p = 0.001 and p < 0.001 respectively; Fig. 6C) and similar to ASCL1, MMP-9 expression remained elevated upon R1881 treatment (Fig. 6C). These findings show key molecular events associated with NE transdifferentiation persist in prostate cancer cells, even following reintroduction of androgen and reversal in morphology
Summary
Neuroendocrine prostate cancer (NEPC) is thought to arise as prostate adenocarcinoma cells transdifferentiate into neuroendocrine (NE) cells to escape potent anti-androgen therapies the exact molecular events accompanying NE transdifferentiation and their plasticity remain poorly defined. NE cells may not fully revert to an epithelial state and retain key NE-like features, suggesting a “hybrid” phenotype This could fuel greater NE transdifferentiation, therapeutic resistance and NEPC evolution upon subsequent androgen deprivation. Such knowledge could facilitate CRPC tumour stratification and identify targets for more effective NEPC management. Resistance to ADT invariably arises and the tumour relapses as aggressive, castration-resistant prostate cancer (CRPC)[3]; a significant clinical challenge due to a lack of therapeutic targets to treat CRPC. The molecular events involved in this “dedifferentiation” and whether NE-like cells within prostate tumours revert to adenocarcinoma cells during breaks in iADT, is unknown
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