Amoeboid Membrane Dynamics in Prostate Cancer

前列腺癌中的阿米巴膜动力学

基本信息

批准号：
8617250
负责人：
Michael R Freeman
金额：
$ 38.46万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-15 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8617250
关键词：
Ablation Actins Adenocarcinoma Cell Affect Anabolism Androgen Receptor Androgen Therapy Androgens Animal Model Behavior Biological Biological Markers Castration Cause of Death Cell membrane Characteristics Chemoprevention Cholesterol Chromosomal Loss Clinical Code Data Disease Disease Progression Disease Resistance Down-Regulation EGFR gene Elements Epidermal Growth Factor Receptor Evaluation Fatty Acids Frequencies Genes Goals Hormones Human Infiltration Laboratories Link Lipids Malignant Neoplasms Malignant neoplasm of prostate Mediating Membrane Membrane Microdomains Mesenchymal Metabolic Metabolic Pathway Metastasis Suppressor Proteins Metastatic Prostate Cancer Metastatic to Modeling Morbidity - disease rate Neoplasm Metastasis North America Organ Pain Pathway interactions Patients Pattern Phenotype Positioning Attribute Property Prostate Prostate Adenocarcinoma Prostatic Neoplasms Protease Inhibitor Proteins Publishing RNA Receptor Activation Receptor Protein-Tyrosine Kinases Resistance Role Series Signal Transduction Site Skeleton Solid Neoplasm Study models System Testing Therapeutic Intervention Up-Regulation advanced disease base cancer cell cost effective therapy implantation improved in vivo inhibitor/antagonist insight lipid biosynthesis lipid metabolism member neoplastic cell network models novel oncogene addiction particle prognostic prostate cancer cell protein expression public health relevance research study success tumor tumor growth tumor microenvironment tumor progression

项目摘要

DESCRIPTION (provided by applicant): Prostate adenocarcinoma (PCa) is a leading cause of death from cancer and there is no effective treatment for "castration-resistant" disease. This project is based on our recent findings that an actin-nucleating protein, Diaphanous related formin-3 (DRF3), is an inhibitor of the "amoeboid" phenotype in human PCa cells, and that chromosomal loss at the DRF3 coding locus occurs at high frequency in metastatic but not primary disease. Functional studies have demonstrated that DRF3 is a member of the EGF receptor (EGFR) network and is positioned at a signaling node that controls the transition from mesenchymal to amoeboid cancer cell phenotypes. The mesenchymal-amoeboid transition (MAT) has recently been identified as a dynamic phenotypic shift that can affect migration of tumor cells through matrices and reduce their sensitivity to protease inhibitors. DRF3 also inhibits the secretion of bioactive microvesicles capable of altering the tumor microenvironment and associates with cholesterol-rich lipid raft membrane microdomains. These data suggest that the DRF3 network may be sensitive to cholesterol- or fatty acid-targeting therapies and/or chemoprevention, which have shown promise in human studies and animal models. We will test the hypothesis that amoeboid properties arising from DRF3 loss results in a more aggressive phenotype. We further hypothesize that amoeboid behavior coincides with upregulation of lipid anabolism and that amoeboid tumor cells may become addicted to lipid-dependent pathways. Thirdly, we hypothesize that a distinct amoeboid signaling network exists and that components of this network may represent novel tumor biomarkers. The specific aims are: Aim 1. Determine the biological consequences of DRF3 loss in prostate cancer. The role of androgen, the androgen receptor, and ERBB receptor tyrosine kinase signaling in the amoeboid phenotype will be determined in the context of DRF3 silencing. We will assess whether DRF3 actively mediates the transition to the mesenchymal phenotype. The effect of DRF3 silencing on tumor growth, metastasis, and sensitivity to ERBB- and cholesterol-targeting therapy, and androgen ablation will be assessed. Patterns of DRF3 expression in human prostate cancers will be evaluated and correlated with clinical parameters. Aim 2. Identify the signaling network that mediates the mesenchymal-amoeboid transition in prostate cancer. A series of directed as well as unbiased experiments, evaluating perturbations in RNA, protein, and palmitoyl-protein networks under conditions of stable DRF3 silencing and EGFR activation will be employed to uncover the signaling network controlling the MAT in prostate cancer cells. Models will be constructed from these data and validated to identify a small series of informative indicators of the MAT. These markers will be used to determine whether the amoeboid phenotype can be detected in vivo using a state-of-the-art platform relevant to prognostic evaluation. These studies will provide new insight into the relationship between membrane dynamics, lipid metabolism and PCa progression to lethal disease.

描述（由申请人提供）：前列腺癌（PCa）是癌症死亡的主要原因，并且对于“去势抵抗”疾病没有有效的治疗方法。该项目基于我们最近的发现，即肌动蛋白成核蛋白，透明相关的 formin-3 (DRF3)，是人类 PCa 细胞中“变形虫”表型的抑制剂，并且 DRF3 编码位点的染色体丢失发生在高转移性疾病而非原发性疾病的频率。功能研究表明，DRF3 是 EGF 受体 (EGFR) 网络的成员，位于控制从间充质癌细胞表型向变形虫癌细胞表型转变的信号传导节点。间充质-变形虫转变（MAT）最近被确定为一种动态表型转变，可以影响肿瘤细胞通过基质的迁移并降低其对蛋白酶抑制剂的敏感性。 DRF3 还抑制能够改变肿瘤微环境的生物活性微泡的分泌，并与富含胆固醇的脂筏膜微域相关。这些数据表明，DRF3 网络可能对胆固醇或脂肪酸靶向治疗和/或化学预防敏感，这些治疗和/或化学预防已在人类研究和动物模型中显示出前景。我们将检验以下假设：DRF3 缺失所产生的变形虫特性会导致更具攻击性的表型。我们进一步假设变形虫行为与脂质合成代谢的上调一致，并且变形虫肿瘤细胞可能对脂质依赖性途径上瘾。第三，我们假设存在独特的变形虫信号网络，并且该网络的组成部分可能代表新的肿瘤生物标志物。具体目标是：目标 1. 确定前列腺癌中 DRF3 缺失的生物学后果。雄激素、雄激素受体和 ERBB 受体酪氨酸激酶信号在变形虫表型中的作用将在 DRF3 沉默的背景下确定。我们将评估 DRF3 是否主动介导向间充质表型的转变。将评估 DRF3 沉默对肿瘤生长、转移以及对 ERBB 和胆固醇靶向治疗以及雄激素消融的敏感性的影响。将评估人类前列腺癌中 DRF3 的表达模式并将其与临床参数相关联。目标 2. 确定介导前列腺癌间充质-变形虫转变的信号网络。一系列定向且无偏见的实验，评估在稳定 DRF3 沉默和 EGFR 激活条件下 RNA、蛋白质和棕榈酰蛋白网络的扰动，将用于揭示控制前列腺癌细胞中 MAT 的信号网络。将根据这些数据构建模型并进行验证，以识别 MAT 的一小组信息指标。这些标记将用于确定是否可以使用与预后评估相关的最先进的平台在体内检测到阿米巴表型。这些研究将为膜动力学、脂质代谢和 PCa 进展为致命疾病之间的关系提供新的见解。