Abstract 3017: A spontaneous developmental lineage plasticity that underlies the response of prostate cancer cells to androgen deprivation

Abstract

Abstract Androgen-dependent prostate cancer (PCa) cells can acquire features of neuroendocrine- (NE-) cells under acute androgen deprivation (AD). Gene expression studies show that other neuroectodermal/mesenchymal (NE/M) cell phenotypes develop under chronic AD. We propose that a transient PCa stem-like cell mediates these transdifferentiations and we sought to reveal and maintain this stem-like state using a special growth medium that is compatible with stem cells that could give rise to these complex lineages. LNCaP or CWR22r cells were plated at low density on coated plates then switched to an androgen-free “stem-transition medium” compatible with NE/M-derived stem cells. Eight days later, cells were transferred in the same medium and were characterized for morphology and 3-dimensional (3D) growth properties. Growth in the medium converted these cells, en masse, to small, rounded proliferating cells that grew as 3D rosettes then to spheroids. Gene expression and cell surface CD antigen profiling of converted LNCaP cells were most consistent with a neural/neural crest stem-like (N/NCSL) identity. N/NCSL PCa cells fail to express androgen receptor (AR) or PSA protein and they are significantly more resistant to hypoxia and enzalutamide than parental LNCaPs. LNCaP-N/NCSL cells have significantly increased tumor-initiating capability and formed tumors in nude mice from only 100 xenografted cells vs 1 X 106 parental LNCaP cells needed to form tumors. When LNCaP N/NCSL cells were placed into differentiation mediums without androgen, they acquired morphological features and expressed biomarkers of neuron-, glia-, oligodendrocyte or osteocyte-like cells. When they were redifferentiated in androgen-containing medium, they reverted to an epithelial cell that resembles parental LNCaPs but they overexpressed AR and retained expression of nestin, a neural stem marker. Our outcomes show that differentiated (AR+) PCa cells have a previously unsuspected developmental plasticity that allows them to return back to a neural/neural crest stem-like state with drastically increased tumor initiating capability under certain microenvironmental conditions. Our new model cell culture system allows us to maintain them in this state or to differentiate them to a variety of NE/M-derived cell lineages. Reactivation of androgen signaling, however, returns them to a modified prostate epithelial-like state that overexpresses AR and retains expression of some stem genes. We believe that our model culture system reveals a novel pathway associated with progression of PCa to therapy-resistance. *Authors contributed equally Citation Format: Josselin Caradec*, Amy Lubik*, Mannan Nouri, Na Li, Jennifer Bishop, Martin Gleave, Ralph Buttyan. A spontaneous developmental lineage plasticity that underlies the response of prostate cancer cells to androgen deprivation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3017. doi:10.1158/1538-7445.AM2014-3017