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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：
10415051
负责人：
Izabela Podgorski
金额：
$ 40.62万
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/10415051
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 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 Model 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 patient derived xenograft model 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.

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