Targeting tumor cell macrophage lipid interactions to overcome resistance to androgen receptor targeted therapy

摘要 肿瘤相关巨噬细胞是促进前列腺癌进展的关键效应免疫细胞。 对其他癌症的研究表明，巨噬细胞分泌细胞因子、血管生成介质和/或代谢物， 对各种疗法产生抗药性。在这里，我们试图确定巨噬细胞改变代谢的作用， 在驱动雄激素受体（AR）靶向治疗的阻力。前列腺的无偏转录组学分析 巨噬细胞耗竭后的肿瘤显示巨噬细胞浸润与分子水平相关， AR激活和胆固醇转运的信号。这些发现在体外被概括，与共同的， 培养巨噬细胞和前列腺癌细胞增强AR核定位，增加癌细胞 在雄激素剥夺条件下的增殖，并降低对AR拮抗剂恩杂鲁胺的敏感性。我们 然后表征胆固醇在巨噬细胞肿瘤细胞脂质相互作用和AR活化中的作用， 胆固醇代谢转录调节因子LXR作为巨噬细胞诱导AR新介质 activation.因此，我们假设前列腺癌中巨噬细胞代谢的改变驱动了耐药性， 涉及通过LXR依赖性干扰胆固醇转运和生物合成的AR靶向治疗。的 胆固醇交换可能进一步推动了金属离子在肿瘤微环境中的可用性， 发现建议。为了解决这个问题，我们建议1）确定巨噬细胞驱动的机制 雄激素受体靶向治疗的抵抗。2)评价靶向治疗的潜力 巨噬细胞-肿瘤细胞脂质相互作用以克服对AR抑制剂的抗性。该项目的目标是 鉴定肿瘤微环境中代谢负债，其可以靶向实现前列腺癌的治愈 患者

Abstract Tumor-associated macrophages are key effector immune cells that promote prostate cancer progression. Studies in other cancers show that macrophage secrete cytokines, angiogenic mediators and/or metabolites to drive resistance to various therapeutics. Here we sought to determine the role of macrophage altered metabolism in driving resistance to androgen receptor (AR) targeted therapy. Unbiased transcriptomic analysis of prostate tumors following macrophage depletion revealed that macrophage infiltration was associated with molecular signatures of AR activation and cholesterol transport. These findings were recapitulated in vitro, with the co- culture of macrophages and prostate cancer cells enhancing AR nuclear localization, increasing cancer cell proliferation in androgen-deprived conditions, and reducing sensitivity to the AR antagonist, enzalutamide. We then characterized role of cholesterol in macrophage tumor cell lipid interaction and AR activation and identified the transcriptional regulator of cholesterol metabolism LXR as a novel mediator of macrophage-induced AR activation. Accordingly, we hypothesize that altered macrophage metabolism in prostate cancer drives resistance to AR-targeted therapy via LXR dependent perturbation of cholesterol transport and biosynthesis. The cholesterol exchange may be further propelled by metal ion availability in tumor microenvironment as our new findings suggested. To address this, we propose to 1) Determine the mechanisms by which macrophages drive resistance to androgen receptor targeted therapy. 2) To evaluate the therapeutic potential of targeting macrophage-tumor cell lipid interactions to overcome resistance to AR inhibitors. The goal of this project is to identify metabolic liabilities in tumor microenvironment that can be targeted to achieve cure in prostate cancer patients.