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

靶向肿瘤细胞巨噬细胞脂质相互作用以克服对雄激素受体靶向治疗的耐药性

基本信息

批准号：
10651105
负责人：
Asmaa Elkenawi
金额：
$ 42.31万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-14 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10651105
关键词：
27-hydroxycholesterol Address Adopted Anabolism Androgen Receptor Androgens Antitumor Response Automobile Driving Binding Biological Assay Biological Markers Cancer Patient Cell Communication Cell Line Cell Proliferation Cells Cholesterol Cholesterol Homeostasis Clinical Clinical Data Coculture Techniques DNA Sequence Alteration Data Disease Drug resistance Equilibrium Family Generations Genes Genetic Transcription Goals Immune Immunocompetent Immunocompromised Host Immunofluorescence Immunologic In Vitro Infiltration Ions Iron LXRalpha protein Lipids Liver X Receptor Macrophage Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of prostate Mediator Metabolic Metabolism Metals Molecular Profiling Nuclear Receptors Patients Phenotype Population Production Promoter Regions Prostatic Neoplasms RNA Receptor Activation Receptor Signaling Reporting Resistance Role Sampling Steroid biosynthesis System Therapeutic Therapeutic Intervention Tumor-associated macrophages Validation Work advanced disease androgen deprivation therapy antagonist anticancer research cancer cell castration resistant prostate cancer cholesterol biosynthesis chromatin immunoprecipitation cytokine enzalutamide extracellular improved in vivo inhibitor loss of function metabolomics mouse model neoplastic cell novel prospective prostate cancer cell prostate cancer progression resistance mechanism response six transmembrane epithelial antigen of the prostate 4 targeted treatment therapy resistant transcription factor transcriptomics tumor tumor microenvironment

项目摘要

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.

抽象的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/或代谢物以驱动对各种治疗的耐药性。在这里，我们试图确定巨噬细胞改变代谢的作用驱动对雄激素受体（AR）靶向治疗的耐药性。前列腺的无偏转录组分析巨噬细胞耗竭后的肿瘤显示巨噬细胞浸润与分子 AR 激活和胆固醇转运的特征。这些发现在体外得到了重现，巨噬细胞和前列腺癌细胞培养增强 AR 核定位，增加癌细胞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节因子 LXR 作为巨噬细胞诱导 AR 的新型介质激活。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 LXR 依赖性扰动胆固醇转运和生物合成来进行 AR 靶向治疗。这肿瘤微环境中金属离子的可用性可能进一步推动胆固醇交换，作为我们的新研究研究结果表明。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产生耐药性。 2）评估靶向治疗潜力巨噬细胞-肿瘤细胞脂质相互作用以克服对 AR 抑制剂的耐药性。该项目的目标是确定肿瘤微环境中的代谢负债，可用于实现前列腺癌的治愈患者。