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:8206771
- 负责人:
- 金额:$ 39.65万
- 依托单位:
- 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 2015-01-31
- 项目状态:已结题
- 来源:
- 关键词:AblationActinsAdenocarcinoma CellAffectAnabolismAndrogen ReceptorAndrogen TherapyAndrogensAnimal ModelBehaviorBiologicalBiological MarkersCastrationCause of DeathCell membraneCharacteristicsChemopreventionCholesterolChromosomal LossClinicalCodeDataDiseaseDisease ProgressionDisease ResistanceDown-RegulationEGFR geneElementsEpidermal Growth Factor ReceptorEvaluationFatty AcidsFrequenciesGenesGoalsHormonesHumanInfiltrationLaboratoriesLinkLipidsMalignant NeoplasmsMalignant neoplasm of prostateMediatingMembraneMembrane MicrodomainsMesenchymalMetabolicMetabolic PathwayMetastasis Suppressor ProteinsMetastatic Prostate CancerMetastatic toModelingMorbidity - disease rateNeoplasm MetastasisNorth AmericaOrganPainPathway interactionsPatientsPatternPhenotypePositioning AttributePropertyProstateProstate AdenocarcinomaProstatic NeoplasmsProtease InhibitorProteinsPublishingRNAReceptor ActivationReceptor Protein-Tyrosine KinasesResistanceRoleSeriesSignal TransductionSiteSkeletonSolid NeoplasmStudy modelsSystemTestingTherapeutic InterventionUp-Regulationadvanced diseasebasecancer cellcosteffective therapyimplantationimprovedin vivoinhibitor/antagonistinsightlipid biosynthesislipid metabolismmemberneoplastic cellnetwork modelsnoveloncogene addictionparticleprognosticprotein expressionpublic health relevanceresearch studysuccesstumortumor growthtumor 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.
PUBLIC HEALTH RELEVANCE: This proposal originates from the recent discoveries by the Freeman laboratory that an actin-nucleating protein, Diaphanous related formin-3 (DRF3), is an inhibitor of the "amoeboid" tumor phenotype and that chromosomal loss at the gene encoding DRF3 occurs with high frequency in patients with metastatic prostate cancer. DRF3 protein expression also declines with disease progression. The mesenchymal-amoeboid transition (MAT) has recently been identified as a dynamic phenotypic transition that can affect migration of tumor cells through matrices and reduce their sensitivity to protease inhibitors. Our data indicate that DRF3 is positioned at a signal transduction node that controls the MAT. Thus, DRF3 has the characteristics of a novel type of tumor- or metastasis-suppressor protein. Our data suggest that this network is linked to anabolic lipogenesis, a feature of aggressive tumor cells. The metabolic phenotype of tumor cells with amoeboid properties may make them vulnerable to therapeutic interventions that target cholesterol or lipid metabolic pathways. Our goals are to determine the biological consequences of DRF3 downregulation in prostate cancer, and to uncover the MAT signaling network that responds to DRF3 silencing. These studies will provide new insight into the relationship between membrane dynamics, lipid metabolism and castrate-resistant prostate cancer. DRF3 loss and the MAT may also be functionally important in other solid tumor systems. Consequently, these studies may provide information of more general significance to human cancer.
描述(由申请人提供):前列腺癌(PCa)是癌症死亡的主要原因,并且没有有效的治疗“去势抵抗”疾病。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DRF 3(DRF 3),是人类PCa细胞中“变形虫”表型的抑制剂,并且DRF 3编码基因座的染色体丢失在转移性而非原发性疾病中以高频率发生。功能研究表明,DRF 3是EGF受体(EGFR)网络的成员,位于控制间充质癌细胞表型向阿米巴样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。DRF 3还抑制能够改变肿瘤微环境的生物活性微囊泡的分泌,并与富含胆固醇的脂筏膜微区相关。这些数据表明,DRF 3网络可能对胆固醇或脂肪酸靶向治疗和/或化学预防敏感,这在人类研究和动物模型中显示出了希望。我们将检验DRF 3缺失引起的变形虫性质导致更具侵袭性表型的假设。我们进一步假设,变形虫的行为与脂质拮抗剂的上调相一致,变形虫肿瘤细胞可能对脂质依赖性途径上瘾。第三,我们假设存在一个独特的变形虫信号网络,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DRF 3丢失的生物学后果。将在DRF 3沉默的背景下确定雄激素、雄激素受体和ERBB受体酪氨酸激酶信号传导在变形虫表型中的作用。我们将评估DRF 3是否积极介导向间充质表型的转变。将评估DRF 3沉默对肿瘤生长、转移和对ERBB和胆固醇靶向治疗的敏感性以及雄激素消融的影响。将评估人前列腺癌中DRF 3表达的模式并将其与临床参数相关联。目标二。识别介导前列腺癌间质-阿米巴样转变的信号网络。一系列定向和无偏实验,评估在稳定的DRF 3沉默和EGFR激活条件下RNA,蛋白质和棕榈酰蛋白质网络的扰动,将用于揭示控制前列腺癌细胞中MAT的信号网络。将根据这些数据建立模型,并加以验证,以确定一小系列的MAT信息指标。这些标志物将用于确定是否可以使用与预后评估相关的最先进平台在体内检测到阿米巴样表型。这些研究将为膜动力学、脂质代谢和PCa进展为致死性疾病之间的关系提供新的见解。
公共卫生关系:这一提议源于Freeman实验室最近的发现,即肌动蛋白成核蛋白,透明相关蛋白3(DRF 3),是“变形虫”肿瘤表型的抑制剂,并且在转移性前列腺癌患者中编码DRF 3的基因处的染色体丢失以高频率发生。DRF 3蛋白表达也随着疾病进展而下降。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。我们的数据表明,DRF 3位于控制MAT的信号转导节点。因此,DRF 3具有新型肿瘤或转移抑制蛋白的特征。我们的数据表明,这个网络与合成代谢脂肪生成有关,这是侵袭性肿瘤细胞的一个特征。具有变形虫性质的肿瘤细胞的代谢表型可能使它们容易受到靶向胆固醇或脂质代谢途径的治疗干预。我们的目标是确定前列腺癌中DRF 3下调的生物学后果,并揭示响应DRF 3沉默的MAT信号网络。这些研究将为膜动力学、脂质代谢和去势抵抗性前列腺癌之间的关系提供新的见解。DRF 3丢失和MAT在其他实体瘤系统中也可能具有重要的功能。因此,这些研究可能提供对人类癌症更普遍意义的信息。
项目成果
期刊论文数量(0)
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Michael R Freeman其他文献
HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN K IS A NOVEL REGULATOR OF ANDROGEN RECEPTOR TRANSLATION IN PROSTATE CANCER
- DOI:
10.1016/s0022-5347(08)60542-x - 发表时间:
2008-04-01 - 期刊:
- 影响因子:
- 作者:
Nishit Mukhopadhyay;Jayoung Kim;Bekir Cinar;Aruna Ramachandran;Martin Hager;Rosalyn M Adam;Pradip Raychaudhuri;Arrigo De Benedetti;Michael R Freeman - 通讯作者:
Michael R Freeman
Propranolol withdrawal in angina pectoris: a prospective study.
心绞痛中的普萘洛尔戒断:一项前瞻性研究。
- DOI:
10.1016/0002-8703(79)90428-9 - 发表时间:
1979 - 期刊:
- 影响因子:4.8
- 作者:
Martin G. Myers;Michael R Freeman;Zulfikar A Juma;G. Wisenberg - 通讯作者:
G. Wisenberg
CAVEOLIN-1 INTERACTS WITH A LIPID RAFT-ASSOCIATED POPULATION OF FATTY ACID SYNTHASE IN PROSTATE CANCER
- DOI:
10.1016/s0022-5347(08)61340-3 - 发表时间:
2008-04-01 - 期刊:
- 影响因子:
- 作者:
Dolores Di Vizio;Rosalyn M Adam;Jayoung Kim;Keith R Solomon;Robert Kim;Federica Sotgia;Michael P Lisanti;Massimo Loda;Mark A Rubin;Francesca Demichelis;Michael R Freeman - 通讯作者:
Michael R Freeman
Michael R Freeman的其他文献
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