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

前列腺癌患者的治疗在很大程度上依赖于剥夺肿瘤细胞 雄激素受体(AR)的转录活性。尽管它们最初有效，但雄激素剥夺 抗去势前列腺癌(CRPC)的出现最终绕过了治疗(ADT)， 其特点是90%以上的患者出现骨转移。 我们最近证明，大约30%的骨转移前列腺癌细胞缺乏AR (Arneg)和表达白细胞介素1β(IL-1β)。我们的假设是，ARNeg癌细胞通过分泌IL-1β， 建立支持性的骨骼栖息地，使ARPos细胞能够承受雄激素剥夺和AR抑制。 因此，这项提案的一个主要目标是确定ARNeg/IL-1β癌细胞维持的方式 去雄激素条件下前列腺癌的骨骼定植。 该建议由三个目标构成：目标1.IL-1β参与ADT抵抗；目标2.骨的作用 目的3.AR对IL-1ββ表达的调节。 拟议的研究将使用转移的动物模型、人类细胞系、PDX来源的细胞和 人体组织样本以确定IL-1β在前列腺癌细胞骨骼定植中的功能作用， 区分对癌细胞的直接自分泌-旁分泌作用和靶向肿瘤细胞- 相关的骨基质。此外，我们将鉴定以IL-1β为靶点的骨基质细胞，并评估 IL-1β诱导AR信号转导及AR-1表达的三种基质因子 受调控的基因。最后，我们将结合分子生物学方法来定义这种机制。 通过AR对IL-1β的转录调节以及通过以下途径对该细胞因子的翻译控制 MiRNAs。 我们的研究将确定ARNeg前列腺癌细胞在转移中的独特作用，并提供概念性和 临床前的基础，补充战略，以改善治疗结果。

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.