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/或代谢物来 引发对各种疗法的抵抗力。在这里，我们试图确定巨噬细胞代谢改变的作用。 在对雄激素受体(AR)靶向治疗产生耐药性方面。前列腺癌的无偏转录分析 巨噬细胞耗竭后的肿瘤显示巨噬细胞的侵袭与分子相关 AR激活和胆固醇运输的信号。这些发现是在体外总结出来的，与合作的-- 巨噬细胞和前列腺癌细胞培养增强AR核定位，增加癌细胞 在雄激素缺乏的条件下增殖，并降低对AR拮抗剂苯扎鲁胺的敏感性。我们 然后表征了胆固醇在巨噬细胞肿瘤细胞脂质相互作用和AR激活中的作用并确定 胆固醇代谢的转录调控因子LXR作为巨噬细胞诱导的AR的新介质 激活。因此，我们假设前列腺癌中巨噬细胞代谢的改变会导致耐药性。 通过依赖LXR的胆固醇转运和生物合成的扰动来进行AR靶向治疗。这个 肿瘤微环境中金属离子的可用性可能会进一步推动胆固醇交换，因为我们的新 研究结果表明。为了解决这个问题，我们建议1)确定巨噬细胞驱动的机制 对雄激素受体靶向治疗的抵抗。2)评估靶向治疗的潜力 巨噬细胞-肿瘤细胞脂质相互作用以克服对AR抑制剂的耐药性。这个项目的目标是 确定肿瘤微环境中可靶向治愈前列腺癌的代谢风险 病人。

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.