Atypical PKC signaling in lung cancer stem cells
肺癌干细胞中的非典型 PKC 信号传导
基本信息
- 批准号:8244684
- 负责人:
- 金额:$ 8.42万
- 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:2010-07-01 至 2012-06-30
- 项目状态:已结题
- 来源:
- 关键词:AlveolarAurothiomalateBehaviorCancer EtiologyCancer PatientCell LineCellsCessation of lifeChromatinDataEpigenetic ProcessExhibitsGenesGeneticGoalsGrowthHomologous GeneHumanHuman ResourcesIn VitroLungLung AdenocarcinomaLung NeoplasmsMaintenanceMalignant NeoplasmsMalignant neoplasm of lungMediatingMouse ProteinNon-Small-Cell Lung CarcinomaOncogenesOncogenicPathway interactionsPatientsPlayPolycombProcessPrognostic MarkerPropertyProtein KinaseProtein Kinase CRoleSignal PathwaySignal TransductionSquamous Cell Lung CarcinomaStem cellsTestingTherapeutic AgentsTransgenic MiceTranslatingTumor-DerivedTumorigenicityUnited Statesatypical protein kinase Cbasecancer initiationcancer stem cellcell growthcell transformationgenetic manipulationin vivoin vivo Modelinhibitor/antagonistinsightlung tumorigenesisnew therapeutic targetnovelnovel therapeuticsprognosticself-renewalstemstem cell nichetherapeutic targettissue resourcetooltreatment strategytumortumor growthtumorigenic
项目摘要
Project Summary
The goals of this project are to elucidate protein kinase C (PKC) signaling mechanisms that contribute to lung
cancer initiation and maintenance and translate these mechanistic insights into better prognostic and treatment
strategies. We recently identified the atypical PKCi gene PRKCI as a human oncogene in the lung.
Furthermore, we find that the mouse PKCi gene Prkci is required for the very earliest steps of lung
tumorigenesis induced by oncogenic Kras in vivo. Specifically, Prkci is necessary for Kras-mediated
transformation of bronchio-alveolar stem cells (BASCs), the putative cell of origin of Kras-mediated lung
tumorigenesis. Genetic disruption of Prkci, or treatment with the PKC¿ inhibitor aurothiomalate (ATM), blocks
Kras-mediated expansion and morphological transformation of BASC in vitro and in vivo, and lung tumor
growth in vivo. Preliminary results suggest that Kras-, Prkci-mediated expansion of BASCs involves induction
of the polycomb gene Bmi1. Bmi1 is an epigenetic chromatin modifier/transcriptional regulator implicated in
cancer stem cell identity and self-renewal. Like Prkci, Bmi1 is necessary for Kras-mediated BASC expansion
and lung tumorigenesis. Based on these preliminary data, we hypothesize that Prkci drives Kras-mediated
BASC transformation and lung tumorigenesis, at least in part, through activation of the Bmi1 signaling
pathway. We further hypothesize that a similar PKCi-Bmi1 signaling axis plays a critical role in the
maintenance, expansion and tumorigenic potential of human lung cancer stem cells. Finally, we hypothesize
that ATM will effectively inhibit the self-renewal and tumorigenic potential of human lung cancer stem cells. We
will test these hypotheses through completion of two interrelated specific aims. In Aim 1 we will assess the role
of the PKCi-Par6-Ect2-Rac1 signaling axis in BASC transformation and dissect the mechanism of crosstalk
between PKCi and Bmi1 signaling in these cells. In Aim 2 we will determine the role of PKCi and Bmi1
signaling in the self-renewal and tumor initiating activity of lung cancer stem cells. We will develop and
characterize a panel of lung cancer stem cell lines from primary lung tumors. Completion of these studies will
provide important new mechanistic insight into oncogenic PKCi signaling in putative lung cancer stem cells,
enhance our understanding of Kras-mediated lung tumorigenesis, and assess the efficacy of a novel
therapeutic agent that targets a critical oncogenic pathway in lung cancer stem cells. These studies have
important implications for PKCi as a therapeutic target and for the use of ATM as a novel therapeutic for the
treatment of lung cancer.
项目概要
该项目的目标是阐明有助于肺功能的蛋白激酶 C (PKC) 信号传导机制。
癌症的发生和维持,并将这些机制见解转化为更好的预后和治疗
策略。我们最近将非典型 PKCi 基因 PRKCI 鉴定为人类肺部致癌基因。
此外,我们发现小鼠 PKCi 基因 Prkci 是肺的最早步骤所必需的。
体内致癌Kras诱导的肿瘤发生。具体来说,Prkci 对于 Kras 介导是必要的
支气管肺泡干细胞 (BASC) 的转化,这是 Kras 介导的肺的假定起源细胞
肿瘤发生。 Prkci 的基因破坏或用 PKC¿ 抑制剂金硫苹果酸 (ATM) 治疗可阻断
Kras介导的BASC体外和体内扩增和形态转化以及肺肿瘤
体内生长。初步结果表明 Kras、Prkci 介导的 BASC 扩增涉及诱导
多梳基因 Bmi1。 Bmi1 是一种表观遗传染色质修饰剂/转录调节因子
癌症干细胞的身份和自我更新。与 Prkci 一样,Bmi1 对于 Kras 介导的 BASC 扩展是必需的
和肺部肿瘤的发生。根据这些初步数据,我们假设 Prkci 驱动 Kras 介导
BASC 转化和肺肿瘤发生,至少部分是通过 Bmi1 信号传导的激活
途径。我们进一步假设类似的 PKCi-Bmi1 信号轴在
人肺癌干细胞的维持、扩增和致瘤潜力。最后,我们假设
ATM将有效抑制人肺癌干细胞的自我更新和致瘤潜力。我们
将通过完成两个相互关联的具体目标来检验这些假设。在目标 1 中,我们将评估角色
BASC转化中PKCi-Par6-Ect2-Rac1信号轴的研究并剖析串扰机制
这些细胞中 PKCi 和 Bmi1 信号传导之间的关系。在目标 2 中,我们将确定 PKCi 和 Bmi1 的作用
肺癌干细胞自我更新和肿瘤启动活性中的信号传导。我们将开发和
表征一组来自原发性肺肿瘤的肺癌干细胞系。完成这些研究将
为假定的肺癌干细胞中致癌 PKCi 信号传导提供重要的新机制见解,
增强我们对 Kras 介导的肺部肿瘤发生的理解,并评估一种新型药物的功效
针对肺癌干细胞中关键致癌途径的治疗剂。这些研究有
对于 PKCi 作为治疗靶点以及使用 ATM 作为新型治疗药物具有重要意义
肺癌的治疗。
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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Alan P. Fields其他文献
Activation of Na/H exchanger in mesangial cells is associated with translocation of PKC isoforms.
系膜细胞中 Na/H 交换器的激活与 PKC 亚型的易位相关。
- DOI:
10.1152/ajprenal.1993.265.1.f53 - 发表时间:
1993 - 期刊:
- 影响因子:0
- 作者:
R. Saxena;B. A. Saksa;Alan P. Fields;M. B. Ganz - 通讯作者:
M. B. Ganz
A Role for Nuclear Phosphatidylinositol-specific Phospholipase C in the G<sub>2</sub>/M Phase Transition
- DOI:
10.1074/jbc.272.42.26313 - 发表时间:
1997-10-17 - 期刊:
- 影响因子:
- 作者:
Bin Sun;Nicole R. Murray;Alan P. Fields - 通讯作者:
Alan P. Fields
Alan P. Fields的其他文献
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{{ truncateString('Alan P. Fields', 18)}}的其他基金
Investigating cells of origin and oncogenic modifiers of 3q26-driven LUSC
研究 3q26 驱动的 LUSC 的起源细胞和致癌修饰因子
- 批准号:
10593501 - 财政年份:2021
- 资助金额:
$ 8.42万 - 项目类别:
A Genetically Tractable Mouse Model for PRKCI-driven Lung Squamous Cell Carcinoma
PRKCI 驱动的肺鳞状细胞癌的遗传易控制小鼠模型
- 批准号:
10653913 - 财政年份:2021
- 资助金额:
$ 8.42万 - 项目类别:
A Genetically Tractable Mouse Model for PRKCI-driven Lung Squamous Cell Carcinoma
PRKCI 驱动的肺鳞状细胞癌的遗传易控制小鼠模型
- 批准号:
10296271 - 财政年份:2021
- 资助金额:
$ 8.42万 - 项目类别:
A Genetically Tractable Mouse Model for PRKCI-driven Lung Squamous Cell Carcinoma
PRKCI 驱动的肺鳞状细胞癌的遗传易控制小鼠模型
- 批准号:
10413236 - 财政年份:2021
- 资助金额:
$ 8.42万 - 项目类别:
Therapeutic targeting of Kras-driven Lung Adenocarcinoma
Kras 驱动的肺腺癌的治疗靶向
- 批准号:
9303312 - 财政年份:2016
- 资助金额:
$ 8.42万 - 项目类别:
The pathophysiology and palliation of the paclitaxel-induced acute pain syndrome
紫杉醇诱发的急性疼痛综合征的病理生理学和缓解作用
- 批准号:
8930932 - 财政年份:2014
- 资助金额:
$ 8.42万 - 项目类别:
Combined PKCiota and mTOR inhibition for treatment of advanced squamous lung canc
联合 PKCiota 和 mTOR 抑制治疗晚期鳞状肺癌
- 批准号:
8299006 - 财政年份:2011
- 资助金额:
$ 8.42万 - 项目类别:
Combined PKCiota and mTOR inhibition for treatment of advanced squamous lung canc
联合 PKCiota 和 mTOR 抑制治疗晚期鳞状肺癌
- 批准号:
8110919 - 财政年份:2011
- 资助金额:
$ 8.42万 - 项目类别:
Atypical PKC signaling in lung cancer stem cells
肺癌干细胞中的非典型 PKC 信号传导
- 批准号:
8100459 - 财政年份:2010
- 资助金额:
$ 8.42万 - 项目类别:
Atypical PKC signaling in lung cancer stem cells
肺癌干细胞中的非典型 PKC 信号传导
- 批准号:
7939191 - 财政年份:2010
- 资助金额:
$ 8.42万 - 项目类别:














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