Amoeboid Membrane Dynamics in Prostate Cancer

前列腺癌中的阿米巴膜动力学

• 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
• 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

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）：前列腺腺癌（PCA）是癌症死亡的主要原因，并且没有有效治疗“ castration抗性”疾病。该项目是基于我们最近的发现，即肌动蛋白 - 核蛋白质相关的formin-3（DRF3）是人PCA细胞中“变形虫”表型的抑制剂，而DRF3编码的染色体损失在高频中出现在高频中，但不是原发性疾病。功能研究表明，DRF3是EGF受体（EGFR）网络的成员，位于控制从间充质到变形虫癌细胞表型的过渡的信号传导节点。间充质 - 氨基骨过渡（MAT）最近被确定为一种动态表型转移，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还抑制了能够改变肿瘤微环境并与富含胆固醇富含胆固醇的脂质筏膜微区的生物活性微泡的分泌。这些数据表明，DRF3网络可能对胆固醇或脂肪酸靶向疗法和/或化学预防敏感，这在人类研究和动物模型中表现出了希望。我们将检验以下假设：DRF3损失引起的变形虫特性会导致更具侵略性的表型。我们进一步假设，变形虫行为与脂质合物的上调相吻合，并且变形虫肿瘤细胞可能会上瘾对脂质依赖性途径。第三，我们假设存在一个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型的肿瘤生物标志物。具体目的是：目标1。确定前列腺癌中DRF3损失的生物学后果。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是否会主动介导向间充质表型的过渡。 DRF3沉默对肿瘤生长，转移和对ERBB和胆固醇靶向疗法的敏感性以及雄激素消融的影响。人类前列腺癌中DRF3表达的模式将与临床参数进行评估并相关。 AIM 2。确定介导前列腺癌中间充质 - 氨基骨过渡的信号网络。在稳定的DRF3沉默和EGFR激活的条件下，一系列定向和公正的实验，评估RNA，蛋白质和棕榈酰 - 蛋白质网络中的扰动，将采用EGFR激活来发现控制Prostate癌细胞中MAT的信号网络。模型将从这些数据中构建并进行验证，以确定垫子的一系列信息指标。这些标记将用于确定是否可以使用与预后评估相关的最新平台在体内检测到变形虫表型。这些研究将为膜动力学，脂质代谢和PCA发展与致命疾病之间的关系提供新的见解。

项目成果

Technologies and Challenges in Proteomic Analysis of Protein S-acylation.

• DOI: 10.4172/jpb.1000327
• 发表时间: 2014-09
• 期刊: Journal of proteomics & bioinformatics
• 作者: Zhou B;An M;Freeman MR;Yang W
• 通讯作者: Yang W

MicroRNA-185 and 342 inhibit tumorigenicity and induce apoptosis through blockade of the SREBP metabolic pathway in prostate cancer cells.

• DOI: 10.1371/journal.pone.0070987
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Li X;Chen YT;Josson S;Mukhopadhyay NK;Kim J;Freeman MR;Huang WC
• 通讯作者: Huang WC