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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的：骨骼是前列腺癌（PCA）继发生长的最喜欢的器官。转移性PCA是致命的，推动其在骨骼中进展并导致治疗进化的机制不是理解。人们已经认识到，PCA细胞与骨微环境的相互作用是关键之一负责转移性肿瘤中自适应促生存信号传导的因素。我们自己的初步数据表明在富含脂肪细胞的环境中，例如骨髓，转移性之间的双向串扰肿瘤细胞和脂肪细胞会导致两种细胞类型的重要代谢变化，最终影响肿瘤生长，生存和对治疗的反应。该癌细胞引起的旁分泌串扰的关键后果是1）丙酮酸激酶M2的寡聚和活性改变（PKM2）； 2）介绍白介素1b的转录（IL-1b）; 3）线粒体铁代谢的肿瘤生存促进变化。我们的中心假设是：肿瘤细胞 - 脂肪细胞相互作用增强了转移性进展，而同时通过选择PKM2和 IL1B介导的铁代谢调节。我们提出了一种多面方法，其中包括脂解的小鼠模型，3D培养技术，患者样品和PDX模型，以及最新的蛋白质组学和RNASEQ方法以前检查未开发的机制将脂解与PKM2/IL1β介导的存活率联系起来。我们将在三个目标。在AIM 1中，我们将有条件地删除脂肪细胞中的脂肪细胞甘油三酸酯脂肪酶（ATGL）并研究脂解的分子机制在骨骼中肿瘤进展和对多西他赛的反应。在目标2中，我们将侧重于脂质介导的对PKM2寡聚的影响。我们将使用蛋白质组学方法来映射S酰基化 PKM2上的位点，并确定这种脂质修饰如何调节蛋白激酶活性和肿瘤的磷蛋白质组以支持生长和进展。在AIM 3中，我们将检查转录 PKM2/IL-1B轴的靶标及其在PCA细胞中线粒体铁代谢调节中的作用脂肪细胞暴露。这些目标共同提供了独立有价值和新颖的信息骨髓脂肪组织的生物学及其在调节骨肿瘤微环境中的功能作用和转移进展。我们的工作将揭示肿瘤适应和骨骼生存的新机制并确定新颖的治疗机理目标。