Identifying the Mechanisms Governing Mena-Induced Tumor Cell Dissemination
确定 Mena 诱导的肿瘤细胞传播的控制机制
基本信息
- 批准号:8532666
- 负责人:
- 金额:$ 3.84万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-09-01 至 2014-04-23
- 项目状态:已结题
- 来源:
- 关键词:AccountingActinsAffectAlternative SplicingApoptoticBehaviorBiological AssayBlocking AntibodiesBlood VesselsCancer EtiologyCellsCessation of lifeChemotactic FactorsChemotaxisCoupledDataDevelopmentEarly identificationEndothelial CellsEnvironmentEpidermal Growth FactorEventExtracellular MatrixFamilyGene Expression ProfileGoalsHandHeregulinImmunohistochemistryIn VitroKnowledgeLaser Scanning Confocal MicroscopyLeadLengthLifeLightMalignant Epithelial CellMalignant NeoplasmsMammary NeoplasmsMicroscopyMigration AssayMindMolecularMovementNeedlesNeoplasm MetastasisPatientsPhenotypePlayProcessProtein IsoformsProteinsRoleSignal PathwaySignal TransductionSourceSpecificitySystemTestingUnited StatesWorkbasecell motilitycell typecellular imagingdesignhigh riskin vivoinsightmacrophagemembermigrationneoplastic cellnovel markerresearch studyresponsetumortumor microenvironmentvasodilator-stimulated phosphoprotein
项目摘要
DESCRIPTION (provided by applicant): More than 1 in 3 people will develop cancer in their lifetime, and approximately 1,500 people die from cancer each day in the United States. Metastases, which require invasion and intravasation, are the major causes of cancer-related deaths. Key cytoskeletal, proliferative and apoptotic proteins have been shown to dynamically alter their gene expression patterns during cell invasion and intravasation, suggesting their involvement in regulating some or all of the processes involved in these cell migration phenotypes. These proteins have been termed collectively as the "Invasion Signature". One of the components of the "Invasion Signature" is Mena, a member of the Enabled (Ena)/vasodilator-stimulated phosphoprotein (VASP) family. Ena/VASP proteins are highly conserved regulators of actin dynamics, known to play critical roles in cell migration. Ena/VASP proteins contain several conserved domains that are thought to elicit specificity of Mena function through alternative splicing. Expression of a Mena isoform, MenaINV, sensitizes carcinoma cells to epidermal growth factor (EGF)- induced carcinoma cell invasion and metastasis. In response to lower levels of EGF, expression of MenaINV leads to enhanced metastasis in vivo. Furthermore, expression of MenaINV results in directional movement of carcinoma cells toward blood vessels, increased invadopodium stability, and a 200-fold increase in transendothelial migration (TEM). Expression of another Mena isoform, Mena11a, also results in increased tumor cell migration. Therefore, Mena plays critical roles in invasion and intravasation. Although many roles for Mena in tumor cell metastasis have been discovered, the mechanisms by which Mena-expressing carcinoma cells use to carry out these functions are still unknown. Thus, we will take advantage of a simplified in vitro system for specific control of parameters, as well as an in vivo system developed in our lab to take into account the tumor microenvironment. With these approaches in hand, specifically, I will test the requirement of invadopodia during Mena-induced chemotaxis, invasion and intravasation, and the upstream signaling events that regulate these processes. In particular, I propose the following aims: 1) Determining whether Mena isoform-expressing cells can autonomously chemosense a chemoattractant, and what step(s) of invadopodium formation is critical for chemosensing; 2) Investigating the relationship between Mena-induced chemotaxis and invadopodium formation in vivo; and 3) Identifying the mechanism underlying the 200 fold increase in TEM activity in MenaINV-expressing cells. Ultimately, these experiments will provide insight into the mechanisms governing the observed Mena-induced metastasis in vivo, which may be critical to the development of new anti-metastatic therapies.
描述(由申请人提供):超过三分之一的人在一生中会患上癌症,在美国每天约有1,500人死于癌症。需要侵入和内渗的转移是癌症相关死亡的主要原因。关键的细胞骨架,增殖和凋亡蛋白已被证明动态改变他们的基因表达模式在细胞侵袭和内渗,这表明他们参与调节一些或所有的过程中涉及这些细胞迁移表型。这些蛋白质被统称为“入侵信号”。其中一个组成部分的“入侵签名”是Mena,一个成员的启用(Ena)/血管舒张剂刺激磷蛋白(VASP)家族。Ena/VASP蛋白是高度保守的肌动蛋白动力学调节因子,已知在细胞迁移中起关键作用。Ena/VASP蛋白含有几个保守的结构域,这些结构域被认为通过选择性剪接引起Mena功能的特异性。Mena亚型MenaINV的表达使癌细胞对表皮生长因子(EGF)诱导的癌细胞侵袭和转移敏感。作为对较低水平EGF的响应,MenaINV的表达导致体内转移增强。此外,MenaINV的表达导致癌细胞朝向血管的定向移动,增加的侵袭足稳定性,以及跨内皮迁移(TEM)增加200倍。另一种Mena同种型Mena 11 a的表达也导致肿瘤细胞迁移增加。因此,Mena在入侵和内渗中起关键作用。尽管已经发现了Mena在肿瘤细胞转移中的许多作用,但表达Mena的癌细胞用于执行这些功能的机制仍然未知。因此,我们将利用简化的体外系统进行参数的特定控制,以及我们实验室开发的体内系统,以考虑肿瘤微环境。有了这些方法在手,具体来说,我将测试的要求invadopodia在Mena诱导的趋化性,入侵和内渗,和上游信号事件,调节这些过程。特别是,我提出了以下目标:1)确定表达Mena亚型的细胞是否可以自主化学感应化学引诱物,以及侵入体形成的哪些步骤对化学感应至关重要; 2)研究体内Mena诱导的趋化性和侵入体形成之间的关系; 3)确定表达MenaINV的细胞中TEM活性增加200倍的机制。最终,这些实验将提供对所观察到的Mena诱导的体内转移的机制的洞察,这可能对开发新的抗转移疗法至关重要。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Minna Roh其他文献
Minna Roh的其他文献
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{{ truncateString('Minna Roh', 18)}}的其他基金
Mitochondrial lateral transfer during metastasis
转移过程中的线粒体横向转移
- 批准号:
10319606 - 财政年份:2021
- 资助金额:
$ 3.84万 - 项目类别:
Mitochondrial lateral transfer during metastasis
转移过程中的线粒体横向转移
- 批准号:
10559498 - 财政年份:2021
- 资助金额:
$ 3.84万 - 项目类别:
Cell Biological Mechanisms of Melanoma Cell Motility In Vivo
体内黑色素瘤细胞运动的细胞生物学机制
- 批准号:
9792230 - 财政年份:2018
- 资助金额:
$ 3.84万 - 项目类别:
Cell Biological Mechanisms of Melanoma Cell Motility in vivo
黑色素瘤细胞体内运动的细胞生物学机制
- 批准号:
8891690 - 财政年份:2015
- 资助金额:
$ 3.84万 - 项目类别:
Cell Biological Mechanisms of Melanoma Cell Motility in vivo
黑色素瘤细胞体内运动的细胞生物学机制
- 批准号:
9040118 - 财政年份:2015
- 资助金额:
$ 3.84万 - 项目类别:
Identifying the Mechanisms Governing Mena-Induced Tumor Cell Dissemination
确定 Mena 诱导的肿瘤细胞传播的控制机制
- 批准号:
8366273 - 财政年份:2011
- 资助金额:
$ 3.84万 - 项目类别:
Identifying the Mechanisms Governing Mena-Induced Tumor Cell Dissemination
确定 Mena 诱导的肿瘤细胞传播的控制机制
- 批准号:
8128222 - 财政年份:2011
- 资助金额:
$ 3.84万 - 项目类别:
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