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：
10620789
负责人：
Izabela Podgorski
金额：
$ 39.11万
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/10620789
关键词：
Acylation Adipocytes Adipose tissue Affect Automobile Driving Biology Bone Marrow Bone neoplasms Carrier Proteins Chemoresistance 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 Chelating Agents Iron Chelation Laboratories Link Lipase Lipid Mobilization 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 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 Tumor Promotion Work Xenograft Model adipocyte biology 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 patient derived xenograft model pharmacologic prostate cancer cell prostate cancer progression response stem stoichiometry targeted treatment three dimensional cell culture transcriptome sequencing treatment response 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) 继发性生长的首选器官，转移性 PCa 是致命的。驱动其在骨骼中进展并有助于逃避治疗的机制并不存在人们已经认识到 PCa 细胞与骨微环境的相互作用是关键之一。我们自己的初步数据是导致转移性肿瘤中适应性促生存信号传导的因素。研究表明，在骨髓等富含脂肪细胞的环境中，转移性细胞之间存在双向串扰。肿瘤细胞和脂肪细胞导致两种细胞类型的关键代谢变化，最终影响肿瘤生长，这种癌细胞引发的旁分泌串扰的主要后果是 1) 改变丙酮酸激酶 M2 (PKM2) 的寡聚化和活性，增强白细胞介素 1b 的转录； (IL-1b)；3) 线粒体铁代谢中促进肿瘤存活的变化。假设是：肿瘤细胞-脂肪细胞相互作用增强转移进展，同时通过选择 PKM2 的酶和转录活性来减少对当前治疗的反应 IL1b 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，以及最先进的蛋白质组学和 RNAseq 方法来检查之前将脂肪分解与 PKM2/IL1β 介导的存活联系起来的未探索的机制，我们将在中进行这些研究。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）并研究其在目标 2 中，我们将研究脂肪分解对骨肿瘤进展和多西紫杉醇反应的分子机制。重点关注脂质介导的 PKM2 寡聚化作用，我们将使用蛋白质组学方法来绘制 S-酰化图谱。 PKM2 上的位点并确定这种脂质修饰如何调节蛋白激酶活性以及在目标 3 中，我们将检查肿瘤的磷酸化蛋白质组以支持生长和进展。 PKM2/IL-1b轴的靶标及其在PCa细胞线粒体铁代谢调节中的作用这些目标共同为脂肪细胞暴露提供了独立的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我们的工作将揭示肿瘤适应和骨存活的新机制。并确定新的、机制性的治疗目标。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Use of FVB Myc-CaP cells as an immune competent, androgen receptor positive, mouse model of prostate cancer bone metastasis.

使用 FVB Myc-CaP 细胞作为具有免疫活性、雄激素受体阳性的前列腺癌骨转移小鼠模型。

DOI：
发表时间：
2021-10
期刊：
影响因子：
0
作者：
Wang, Yu;Herroon, Mackenzie K;Zielske, Steven P;Ellis, Leigh;Podgorski, Izabela;Taichman, Russell S;Cackowski, Frank C
通讯作者：
Cackowski, Frank C

Adipocyte-driven unfolded protein response is a shared transcriptomic signature of metastatic prostate carcinoma cells.

脂肪细胞驱动的未折叠蛋白反应是转移性前列腺癌细胞共有的转录组特征。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Herroon, Mackenzie K;Mecca, Shane;Haimbaugh, Ale;Garmo, Laimar C;Rajagurubandara, Erandi;Todi, Sokol V;Baker, Tracie R;Podgorski, Izabela
通讯作者：
Podgorski, Izabela

Guidelines for Biobanking of Bone Marrow Adipose Tissue and Related Cell Types: Report of the Biobanking Working Group of the International Bone Marrow Adiposity Society.

骨髓脂肪组织和相关细胞类型生物样本库指南：国际骨髓肥胖协会生物样本库工作组的报告。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Lucas, Stephanie;Tencerova, Michaela;von der Weid, Benoit;Andersen, Thomas Levin;Attané, Camille;Behler;Cawthorn, William P;Ivaska, Kaisa K;Naveiras, Olaia;Podgorski, Izabela;Reagan, Michaela R;van der Eerden, Bram C J
通讯作者：
van der Eerden, Bram C J