Directional Motility and ERM Scaffolding in Pathfinder Pancreatic Carcinoma Cells
Pathfinder 胰腺癌细胞的定向运动和 ERM 支架
基本信息
- 批准号:8779713
- 负责人:
- 金额:$ 16.64万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-01-01 至 2017-12-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalA kinase anchoring proteinActin-Binding ProteinActinsAddressAdenocarcinoma CellBehaviorBindingBinding ProteinsBiosensorCause of DeathCell membraneCell physiologyCellsComplexCyclic AMP-Dependent Protein KinasesCytoskeletonDevelopmentDiagnosisDiseaseDisease ProgressionDistantDistant MetastasisEnvironmentEpithelial CellsEventExtracellular Matrix DegradationExtracellular Matrix ProteinsFamilyFibroblastsFibronectinsFocal AdhesionsGrowthHumanInterphase CellIntraepithelial NeoplasiaInvadedLabelLeadLifeLinkMalignant Epithelial CellMalignant NeoplasmsMalignant neoplasm of pancreasMediatingMembraneMitogen-Activated Protein KinasesModelingMolecularMutationNeoplasm MetastasisPancreasPancreatic Ductal AdenocarcinomaPancreatic carcinomaPatientsPlayPopulationProcessProductionPropertyProtein FamilyProteinsRecruitment ActivityRegulationRoleScaffolding ProteinSignal PathwaySignal TransductionSiteStagingStress FibersTestingTherapeuticTimeTumor Cell InvasionTumorigenicityValidationbasecancer cellcell motilitycellular imagingcohortezringenetic regulatory proteinin vitro Modelin vivoin vivo Modelinhibitor/antagonistknock-downmembermigrationmoesinmolecular dynamicsmutantneoplastic cellnovelnovel therapeutic interventionpancreatic neoplasmprotein complexpublic health relevanceradixin proteinrapid growthrhoscaffoldstellate celltargeted treatmenttumortumor growth
项目摘要
DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with median survival times of less than a year. Activating KRas mutations are present at diagnosis in up to 95% of patients, with alterations already existing in 92% of early-stage pancreatic intraepithelial neoplasms. In addition, PDAC displays rapid invasion locally, in addition to distant metastasis, processes that require multiple molecular events that are critical to target therapeutically. While the mode of invasion varies among different PDAC cells (ie, single-cell, collective), cells at the leading edge of invasion zones may
develop pathfinder cell functions, which can create the microtracks through which the tumor cells will spread, by degradation of the extracellular matrix (ECM). Actin-rich membrane protrusions (invadopodia) develop in specific cell populations, which lead the migratory cohort of invading cells. Thus, it is critical to understand the mechanisms involved in the formation of these pathfinder cells and the molecular dynamics that occur at the invading edges. Among these events, mutant KRas is required for the formation of invadopodia, and specific cellular scaffolds are required for mediating the effector signaling pathways involved. For example, Ezrin, a scaffold protein that links the plasma membrane to the actin cytoskeleton, as well as other members of the ezrin-radixin-moesin (ERM) family, are present in actin-rich invadopodia and play important roles in PDAC migration. In addition, discrete pools of active RhoA at the leading and lagging edges of motile PDACs are critical for invasive behavior. We have described a novel anti-motility target (km23-1), the depletion of which was shown to diminish Ras and ERK activity, as well as TGFss1 production and cancer cell motility and invasion. It also interacts with numerous actin-regulatory proteins and can modulate RhoA activity and Ezrin expression. We hypothesize that km23-1 plays an important role in the formation and activity of invadopodia by facilitating the assembly of Ezrin- enriched complexes that further regulate Ras activity and protein kinase A (PKA)-modulated RhoA protrusion- retraction events. Therefore, in Aim 1, we will examine the ability of km23-1 depletion to inhibit PDAC invasion in organotypic models representative of the in vivo setting, which will include stromal pancreatic stellate cells.
Additional studies will address the functional role of km23-1 in regulating invadopodia RhoA activity and leader cell migration. Further, since ERM and actin are required for Ras activation, we will test the hypothesis that km23-1 regulates Ezrin scaffolded complexes to control Ras activation and downstream events involved in invadopodia protrusion during PDAC invasion. In Aim 2, we will examine the effect of km23-1 depletion on tumorigenicity and metastasis in vivo to determine the potential utility of km23-1 inhibitors as anti-metastatic therapy. The results of these studies will provide significant new information regarding the spatial control of Ras and RhoA activity, as well as Ezrin/actin scaffolding, in PDAC invasion and metastasis. They will also facilitate efforts to develop novel km23-1- and Ezrin-based inhibitors for the treatment of PDAC.
描述(由申请人提供):胰腺导管腺癌(PDAC)是最致命的恶性肿瘤之一,中位生存时间不到一年。高达95%的患者在诊断时存在激活KRas突变,92%的早期胰腺上皮内肿瘤已经存在改变。此外,除了远处转移外,PDAC还表现出局部快速侵袭,这一过程需要多种分子事件,这些事件对靶向治疗至关重要。虽然不同的PDAC细胞(单细胞、集体)的侵袭方式不同,但侵袭区前沿细胞的侵袭方式可能不同
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Kathleen M Mulder其他文献
Kathleen M Mulder的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Kathleen M Mulder', 18)}}的其他基金
Mechanisms of TGF-Beta Production in Human Cancer Cells
人类癌细胞中 TGF-β 产生的机制
- 批准号:
8073200 - 财政年份:2007
- 资助金额:
$ 16.64万 - 项目类别:
Mechanisms of TGF-Beta Production in Human Cancer Cells
人类癌细胞中 TGF-β 产生的机制
- 批准号:
7472603 - 财政年份:2007
- 资助金额:
$ 16.64万 - 项目类别:
Mechanisms of TGF-Beta Production in Human Cancer Cells
人类癌细胞中 TGF-β 产生的机制
- 批准号:
7841799 - 财政年份:2007
- 资助金额:
$ 16.64万 - 项目类别:
Mechanisms of TGF-Beta Production in Human Cancer Cells
人类癌细胞中 TGF-β 产生的机制
- 批准号:
7628570 - 财政年份:2007
- 资助金额:
$ 16.64万 - 项目类别:
Mechanisms of TGF-Beta Production in Human Cancer Cells
人类癌细胞中 TGF-β 产生的机制
- 批准号:
7321536 - 财政年份:2007
- 资助金额:
$ 16.64万 - 项目类别:
相似海外基金
A-Kinase Anchoring Protein Dysregulation during Alcohol-Associated Liver Disease
酒精相关性肝病期间 A 激酶锚定蛋白失调
- 批准号:
10416315 - 财政年份:2022
- 资助金额:
$ 16.64万 - 项目类别:
A-Kinase Anchoring Protein Dysregulation during Alcohol-Associated Liver Disease
酒精相关性肝病期间 A 激酶锚定蛋白失调
- 批准号:
10705602 - 财政年份:2022
- 资助金额:
$ 16.64万 - 项目类别:
Clustering of individual and diverse ion channels together into complexes, and their functional coupling, mediated by A-kinase anchoring protein 79/150 in neurons
单个和不同的离子通道聚集成复合物,以及它们的功能耦合,由神经元中的 A-激酶锚定蛋白 79/150 介导
- 批准号:
9212929 - 财政年份:2015
- 资助金额:
$ 16.64万 - 项目类别:
Duplin: A Novel A-Kinase Anchoring Protein
Duplin:一种新型 A 激酶锚定蛋白
- 批准号:
7484816 - 财政年份:2008
- 资助金额:
$ 16.64万 - 项目类别:
Duplin: A Novel A-Kinase Anchoring Protein
Duplin:一种新型 A 激酶锚定蛋白
- 批准号:
7676742 - 财政年份:2008
- 资助金额:
$ 16.64万 - 项目类别:
Synemin is an A-Kinase Anchoring Protein in the Heart
Synemin 是心脏中的一种 A 激酶锚定蛋白
- 批准号:
7169231 - 财政年份:2004
- 资助金额:
$ 16.64万 - 项目类别:
Synemin is an A-Kinase Anchoring Protein in the Heart
Synemin 是心脏中的一种 A 激酶锚定蛋白
- 批准号:
6857635 - 财政年份:2004
- 资助金额:
$ 16.64万 - 项目类别:
Synemin is an A-Kinase Anchoring Protein in the Heart
Synemin 是心脏中的一种 A 激酶锚定蛋白
- 批准号:
6994379 - 财政年份:2004
- 资助金额:
$ 16.64万 - 项目类别:
Synemin is an A-Kinase Anchoring Protein in the Heart
Synemin 是心脏中的一种 A 激酶锚定蛋白
- 批准号:
7326774 - 财政年份:2004
- 资助金额:
$ 16.64万 - 项目类别:
ANALYSIS OF PROTEIN KINASE A A KINASE ANCHORING PROTEIN INTERACTIONS
蛋白激酶 A 与激酶锚定蛋白相互作用的分析
- 批准号:
6470644 - 财政年份:2001
- 资助金额:
$ 16.64万 - 项目类别:














{{item.name}}会员




