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: 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
• 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

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）继发性生长的有利器官。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 明白已经认识到，PCa细胞与骨微环境的相互作用是骨微环境的关键之一。 在转移性肿瘤中负责适应性促存活信号传导的因子。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，转移性肿瘤之间的双向串扰， 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， 存活率和对治疗的反应这种癌细胞引发的旁分泌串扰的关键后果是1） 丙酮酸激酶M2（PKM 2）的寡聚化和活性改变; 2）白细胞介素1b的转录增强 （IL-1b）;和3）线粒体铁代谢中的肿瘤存活促进变化。我们的中央 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PKM 2的酶活性和转录活性来降低对当前治疗的反应， IL 1b介导的铁代谢调节。 我们提出了一个多方面的方法，包括脂解的小鼠模型，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，以检查以前的 将脂解与PKM 2/IL 1 β介导的存活联系起来的未探索的机制。我们将进行这些研究， 三个目标。在目的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），并研究其在脂肪细胞中的表达。 脂解作用对骨肿瘤进展的分子机制及对多西他赛的反应。在目标2中， 关注脂质介导的对PKM 2寡聚化的影响。我们将使用蛋白质组学方法来定位S-酰化 PKM 2上的位点，并确定这种脂质修饰如何调节蛋白激酶活性， 磷酸化蛋白质组的肿瘤，以支持生长和进展。在目标3中，我们将研究转录 PKM 2/IL-1b轴的靶点及其在PCa细胞线粒体铁代谢调节中的作用 脂肪细胞暴露。总之，这些目标提供了独立的有价值的和新颖的信息， 骨髓脂肪组织生物学及其在骨肿瘤微环境调节中的作用 和转移性进展。我们的工作将揭示肿瘤在骨中适应和存活的新机制 并确定新的治疗机制靶点。

项目成果

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

• DOI: 10.1016/j.jbo.2021.100386
• 发表时间: 2021-10
• 期刊: Journal of bone oncology
• 影响因子: 3.4
• 作者: Wang Y;Herroon MK;Zielske SP;Ellis L;Podgorski I;Taichman RS;Cackowski FC
• 通讯作者: Cackowski FC

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.

• DOI: 10.3389/fendo.2021.744527
• 发表时间: 2021
• 期刊: Frontiers in endocrinology
• 影响因子: 5.2
• 作者: Lucas S;Tencerova M;von der Weid B;Andersen TL;Attané C;Behler-Janbeck F;Cawthorn WP;Ivaska KK;Naveiras O;Podgorski I;Reagan MR;van der Eerden BCJ
• 通讯作者: van der Eerden BCJ

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

• DOI: 10.1016/j.bbamcr.2021.119101
• 发表时间: 2021-10
• 期刊: Biochimica et biophysica acta. Molecular cell research
• 作者: Herroon MK;Mecca S;Haimbaugh A;Garmo LC;Rajagurubandara E;Todi SV;Baker TR;Podgorski I
• 通讯作者: Podgorski I