Interleukin-1beta and AR-negative tumor cells in metastatic castrate-resistant prostate cancer

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Treatment of prostate cancer patients relies heavily on therapeutic strategies depriving tumor cells of the transcriptional activity of the Androgen Receptor (AR). Despite their initial efficacy, androgen-deprivation therapies (ADT) are eventually circumvented by the emergence of castrate-resistant prostate cancer (CRPC), which is characterized by skeletal metastases in more than 90% of patients. We have recently demonstrated that approximately 30% of bone-metastatic prostate cancer cells lack AR (ARNeg) and express Interleukin-1β (IL-1β). Our hypothesis is that ARNeg cancer cells, by secreting IL-1β, establish a supportive bone habitat, allows ARPos cells to withstand androgen-deprivation and AR inhibition. Thus, a major goal of this proposal is to define the modalities by which ARNeg/IL-1β cancer cells sustain skeletal colonization in prostate cancer under androgen-deprived conditions. This proposal is structured in three aims: Aim 1. IL-1β involvement in ADT resistance; Aim 2. Role of bone stroma in IL-1β induced regulation of ARPos cells; Aim 3. Regulation of IL-1β expression by AR. The proposed studies will employ animal models of metastasis, human cell lines, PDX-derived cells and human tissue amples to ascertain the functional role of IL-1β in skeletal colonization of prostate cancer cells, discriminating between direct autocrine-paracrine effects on cancer cells and targeting cells of the tumor- associated bone stroma. Furthermore, we will identify the bone stroma cells targeted by IL-1β and evaluate three stromal factors secreted in response to IL-1β for the ability to induce AR signaling and expression of AR- regulated genes. Finally, using a combination of molecular biology approaches we will define the mechanism for the transcriptional regulation of IL-1β by the AR and the translational control exerted on this cytokine by miRNAs. Our studies will define the unique role of ARNeg prostate cancer cells in metastases and provide conceptual and pre-clinical ground for complementary strategies to improve therapeutic outcomes.