Activin a as a Novel Anti-Neuroendocrine Tumor Target

Among the metastatic forms of prostate adenocarcinoma (PCa) are those that express neuroendocrine (NE) markers, often referred to as neuroendocrine differentiation (NED) or NE phenotype. NED is seen in ＞30% of PCa and is associated with poor prognosis and androgen independence. By comparing expression profiles of human primary prostate cancer biopsies and androgen refractory metastatic prostate cancer biopsies, we discovered that the expression of activin A is increased in PCa patients with metastatic propensity and correlates with increased PSA expression, and Gleason scores. We further found that NE-like cells, whether they were trans-differentiated from human PCa cell line or human PCa biopsies after androgen deprivation therapy (ADT), express high level of activin A. More interestingly, it was further discovered that the neurite outgrowth of these cells was significantly increased upon activin A treatment with androgen blockade, suggesting a stimulatory role of activin A in their NED. This finding led us to a big challenge since most current ADT of PCa are targeting inhibition of androgen receptor (AR) signaling and it is expected that targeting AR can kill differentiated luminal epithelial cells that comprises still the majority of refractory tumors, but it would allow small population of NE cells that expand higher potential of tumor malignancy. It led us to realize that the failure of ADT might be due to this fact and a development of better understanding of NE tumor formation and strategy to target NE population cells is essential. Therefore, we hypothesize that activin A signaling is required for the formation of PCa with NE phenotype and targeting activin A pathway combined with ADT may eventually block occurrence and growth of hormone refractory PCa. In order to prove our hypothesis, we propose three aims as follows: Aim 1: Use two in vivo mouse models to investigate the roles of activin A on the formation of PCa with NE tumor. First, we will use TRAMP/activin A-conditional KO mice and the transgenic mice expressing probasin-activin βA generated by our lab and examine the NED foci numbers and tumor incidence to prove the roles of activin A in NE tumor formation. Next, the localization and expression level of active forms of FoxA2/Smads proteins will be correlated with NE markers in PCa tumor to determine whether activin A/FoxA2/Smads pathways are activated in prostate NE tumor. Aim 2: To study the mechanisms of FoxA2/Smads signaling-mediated transcriptional programs that are required for activin A-associated NED in PCa. First, we will study whether disruption of Smads/FoxA2 function may affect NED by analyzing NE outgrowth assay and NE markers expression. Next, we will identify a subset of activin A-mediated targeted genes, which are cooperatively regulated by FoxA2/Smads. We will also determine whether MAP-1B gene and identified target genes coregulated by Smads/FoxA2 are essential for activin A-associated NE phenotype of prostate cancer cells. Aim 3: To investigate whether ADT allows activation of activin A signaling to stimulate neuroendocrine cell differentiation and inhibit epithelial cell growth in prostate cancer. We will use more PCa cell lines and in vivo mouse models to confirm androgen blockade promote activin A function in stimulation of neuroendocrine cell differentiation and suppression of epithelial cell growth in PCa. More importantly, we will evaluate the effects of the combined therapy of ADT and activin A inhibitors on blocking occurrence and growth of hormone refractory PCa tumors. Impact: Identification of activin A signaling pathways mediated with NE tumor formation could provide the potential targets for novel hormone refractory PCa therapy. Successful accomplishment of this study will shed new light to battle PCa that ADT therapy alone cannot.

Project ID:PC10401-0160
External Project ID:NSC102-2628-B182-004-MY3