Adipocyte regulation of tumor survival in metastatic prostate cancer: new targets for therapy

脂肪细胞对转移性前列腺癌肿瘤存活的调节：治疗的新靶点

• 批准号: 10033239
• 负责人: Izabela Podgorski
• 金额: $ 41.14万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10033239
• 关键词: Acylation; Adipocytes; Adipose tissue; Affect; Automobile Driving; Biology; Bone Marrow; Bone neoplasms; Carrier Proteins; Culture Techniques; Data; Disease; Environment; Enzymes; Exposure to; Fatty Acids; Fostering; Genetic Transcription; Glycolysis Pathway; Goals; Growth; Interdisciplinary Study; Interleukin-1 beta; Interleukins; Iron; Iron Chelation; Laboratories; Link; Lipase; Lipids; Lipolysis; Malignant Neoplasms; Malignant neoplasm of prostate; Maps; Marrow; Mass Spectrum Analysis; Mediating; Metabolic; Metabolism; Metastatic Prostate Cancer; Mitochondria; Modeling; Modification; Molecular; Molecular Conformation; Neoplasm Metastasis; Obesity; Organ; Oxidative Stress; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmacology; Phenotype; Post-Translational Protein Processing; Process; Protein Kinase; Proteomics; Publishing; Pyruvate Kinase; Regulation; Research; Research Personnel; Resolution; Role; Sampling; Signal Transduction; Signaling Molecule; Site; Site-Directed Mutagenesis; Skeleton; Source; Structure; Testing; Therapeutic Effect; Tissues; Work; Xenograft procedure; adipocyte biology; base; bone; cancer cell; cancer survival; cell type; chemotherapy; dimer; docetaxel; genetic manipulation; heme oxygenase-1; improved; iron metabolism; liquid chromatography mass spectrometry; mitochondrial metabolism; monomer; mouse model; neoplastic cell; new therapeutic target; novel; paracrine; prostate cancer cell; prostate cancer progression; response; stem; stoichiometry; targeted treatment; three dimensional cell culture; transcriptome sequencing; tumor; tumor growth; tumor metabolism; tumor microenvironment; tumor progression; uptake

ABSTRACT: Bone is a favored organ for the secondary growth from prostate cancer (PCa). Metastatic PCa is lethal and the mechanisms that drive its progression in the skeleton and contribute to the evasion of therapy are not understood. It has been recognized that interplay of PCa cells with the bone microenvironment is one of the key factors responsible for the adaptive pro-survival signaling in the metastatic tumor. Our own preliminary data show that in the fat cell-rich environments such as bone marrow, bi-directional cross-talk between metastatic tumor cells and fat cells results in key metabolic changes in both cell types, ultimately affecting tumor growth, survival and response to therapy. The key consequences of this cancer cell-initiated paracrine crosstalk are 1) altered oligomerization and activity of pyruvate kinase M2 (PKM2); 2) enhanced transcription of interleukin 1b (IL-1b) ; and 3) tumor survival-promoting changes in the mitochondrial iron metabolism. Our central hypothesis is that: tumor cell-adipocyte interactions enhance metastatic progression, while simultaneously reducing response to current treatments, by co-opting enzymatic and transcriptional activities of PKM2 and IL1b-mediated regulation of iron metabolism. We propose a multi-faceted approach that includes mouse models of lipolysis, 3D culture techniques, patient samples and PDX models, as well as state-of-the-art proteomics and RNAseq approaches to examine previously unexplored mechanisms linking lipolysis with PKM2/IL1β-mediated survival. We will perform these studies in three Aims. In Aim 1 we will conditionally delete adipocyte triglyceride lipase (ATGL) in adipocytes and study the molecular mechanisms of lipolysis on tumor progression in bone and response to docetaxel. In Aim 2 we will focus on lipid-mediated effects on PKM2 oligomerization. We will use proteomics approaches to map S-acylation sites on PKM2 and determine how this lipid modification regulates protein kinase activity and the phosphoproteome of the tumor to support growth and progression. In Aim 3 we will examine transcriptional targets of PKM2/IL-1b axis and its role in regulation of mitochondrial iron metabolism in PCa cells upon adipocyte exposure. Together, these aims provide independently valuable and novel information into the biology of bone marrow adipose tissue and its functional role in regulating the bone tumor microenvironment and metastatic progression. Our work will reveal new mechanisms of tumor adaptation and survival in bone and identify novel, mechanistic targets for therapy.

摘要： 骨是前列腺癌(Pca)二次生长的重要器官。转移性前列腺癌是致命的，而 在骨骼中推动其进展并有助于逃避治疗的机制并不是 明白了。已经认识到，PCA细胞与骨微环境的相互作用是关键之一 转移性肿瘤中适应性促生存信号的相关因素。我们自己的初步数据 表明在富含脂肪细胞的环境中，如骨髓、转移之间存在双向串扰 肿瘤细胞和脂肪细胞导致这两种细胞的关键代谢变化，最终影响肿瘤的生长。 生存和对治疗的反应。这种癌细胞引发的旁分泌串扰的主要后果是：1) 丙酮酸激酶M2(PKM2)的寡聚和活性改变；2)促进白细胞介素1b的转录 (IL-1b)；以及3)促进肿瘤存活的线粒体铁代谢的变化。我们的中央 假说是：肿瘤细胞-脂肪细胞的相互作用促进转移进展，同时 通过增加PKM2和PKM2的酶和转录活性来减少对当前治疗的反应 IL-1b介导的铁代谢调节。 我们提出了一种多方面的方法，包括小鼠脂肪分解模型、3D培养技术、患者 样本和PDX模型，以及最新的蛋白质组学和RNAseq方法 未探索的机制将脂解与PKM2/IL1β介导的生存联系起来。我们将在以下时间进行这些研究 三个目标。在目标1中，我们将有条件地删除脂肪细胞中的脂肪细胞甘油三酯脂肪酶(ATGL)，并研究 脂肪分解对骨肿瘤进展的分子机制及对多西紫杉醇的反应。在《目标2》中我们将 重点研究脂类对PKM2齐聚的影响。我们将使用蛋白质组学方法来定位S-酰化 并确定这种脂质修饰如何调节蛋白激酶活性和 支持肿瘤生长和进展的磷酸蛋白质组。在目标3中，我们将检查转录 PKM2/IL-1b轴靶点及其在PCa细胞线粒体铁代谢调控中的作用 脂肪细胞暴露。总而言之，这些目标为 骨髓脂肪组织生物学及其对骨肿瘤微环境的调节作用 和转移性进展。我们的工作将揭示肿瘤在骨骼中适应和存活的新机制 并确定新的、机械性的治疗靶点。