Mechanisms that control the progression from premalignant lesions to adenocarcinomas in the lung
Mechanisms that control the progression from premalignant lesions to adenocarcinomas in the lung
批准号:
9459856
负责人:
FERRUCCIO GALBIATI
金额:
$31.25万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-04-01 至 2022-03-31
关键词:
A549AblationAddressAdenocarcinomaBindingBinding ProteinsBiochemicalBypassCAV1 geneCancer EtiologyCancer PatientCell AgingCellsCessation of lifeCollectionDNA DamageDataDevelopmentDown-RegulationEpithelial CellsExperimental DesignsFRAP1 geneFutureGene ExpressionGenesGeneticGenetic ScreeningGrowthGuanine NucleotidesHistologicHomologous GeneHumanIn VitroInvestigationKRAS2 geneKnockout MiceLesionLibrariesLinkLungLung AdenocarcinomaLung NeoplasmsMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of lungMediatingMolecularMusMutationNon-Small-Cell Lung CarcinomaOncogenesOncogenicOxidative StressOxidesPathogenesisPathway interactionsPharmacologyPremalignantPublishingPurinesReactive Oxygen SpeciesScaffolding ProteinSignal TransductionSignaling MoleculeSirolimusSoft Agar AssayTestingTherapeuticTumor Suppressor ProteinsUnited StatesWomancancer cellcancer diagnosiscancer typecaveolin 1genetic approachin vivoinsightmenmigrationmouse modelnovelnovel therapeutic interventionoverexpressionoxidationpreclinical studyprematurepressurepreventprotein Kresponsesenescencesmall hairpin RNAsubcutaneoustumortumor xenografttumorigenic
中文摘要
致癌性K-Ras通过提高细胞内活性氧水平触发细胞衰老。克-拉斯-
表达癌基因的细胞需要绕过癌基因诱导的衰老(OIS)屏障才能进展到更高的级别
恶性肿瘤非小细胞肺癌(NSCLC)是最常见的肺癌形式,
腺癌是最常见的NSCLC类型。K-Ras突变代表了最常见的
肺腺癌的变化。从癌前病变进展为恶性腺癌是一个重要的因素。
NSCLC发病机制的标志。我们提议的调查将直接针对挑衅性
问题#1通过识别和功能性表征新的分子机制,控制
从癌前肺病变向腺癌的转变,并且其抑制有可能预防
NSCLC发展。
中心假设:我们提出了新的范式,即小窝蛋白-1控制肺上皮细胞的命运,
细胞对致癌Ras的反应。我们认为致癌K-Ras诱导癌前病变细胞衰老,
通过小窝蛋白-1介导的促氧化信号传导和小窝蛋白-1的下调导致肺损伤
表达是绕过OIS并驱动向恶性腺癌进展所必需的。
将通过追求三个具体目标来检验这一假设:
目的1:确定小窝蛋白-1如何促进致癌K-Ras诱导的细胞衰老。假设:
致癌K-Ras通过mTOR激活促进小窝蛋白-1对MTH 1功能的抑制,这导致
肺上皮细胞嘌呤氧化增强、持续DNA损伤反应(DDR)和细胞衰老
细胞
目的2:确定致癌K-Ras表达细胞如何绕过OIS。假设:存在选择性压力
在表达致癌K-Ras的细胞中,下调小窝蛋白-1基因表达以逃避OIS。
目的3:确定缺乏小窝蛋白-1是否促进小鼠腺癌的进展
癌基因诱导的肺癌模型。假设:Caveolin-1介导的OIS是肿瘤抑制因子
机制:基因切除小窝蛋白-1抑制癌前病变和衰老阳性细胞的形成。
肺部病变有利于恶性和衰老阴性腺癌。
这些研究提出了靶向绕过OIS的K-Ras依赖性信号传导的新概念
通过下调小窝蛋白-1的表达,这将在本建议中确定,是一种替代方法,
更好的治疗选择,然后靶向K-Ras本身:它将允许选择性抑制促肿瘤发生的K-
Ras信号转导,同时拯救促衰老K-Ras通路。这些新信息有可能直接
影响新型治疗干预措施的开发,以防止进展到肺
腺癌
英文摘要
Oncogenic K-Ras triggers cellular senescence by raising intracellular levels of reactive oxygen species. K-Ras-
expressing cells need to bypass the oncogene-induced senescence (OIS) barrier to progress to higher grades
of malignancy. Non-small cell lung cancer (NSCLC) is the most common form of lung cancer and
adenocarcinoma is the most common type of NSCLC. K-Ras mutations represent the most common molecular
change in lung adenocarcinomas. Progression from pre-malignant lesions to malignant adenocarcinomas is a
hallmark of NSCLC pathogenesis. Our proposed investigations will directly address Provocative
Question #1 by identifying and functionally characterizing novel molecular mechanisms that control the
transition from premalignant lung lesions to adenocarcinomas and whose inhibition has the potential to prevent
NSCLC development.
Central hypothesis: we advance the novel paradigm that caveolin-1 controls the fate of lung epithelial
cells in response to oncogenic Ras. We propose that oncogenic K-Ras induces senescence in premalignant
lung lesions through a caveolin-1-mediated pro-oxidative signaling and that downregulation of caveolin-1
expression is necessary to bypass OIS and drive the progression to malignant adenocarcinomas.
This hypothesis will be tested by pursuing three specific aims:
Aim 1: Determine how caveolin-1 promotes oncogenic K-Ras-induced cellular senescence. Hypothesis:
inhibition of MTH1 function by caveolin-1 is promoted by oncogenic K-Ras via mTOR activation, which leads to
enhanced purine oxidation, sustained DNA damage response (DDR) and cellular senescence in lung epithelial
cells.
Aim 2: Identify how oncogenic K-Ras-expressing cells bypass OIS. Hypothesis: a selective pressure exists
in oncogenic K-Ras-expressing cells that downregulates caveolin-1 gene expression to elude OIS.
Aim 3: Determine if a lack of caveolin-1 promotes the progression to adenocarcinomas in mouse
models of oncogene-induced lung cancer. Hypothesis: Caveolin-1-mediated OIS is a tumor suppressor
mechanism: the genetic ablation of caveolin-1 inhibits the formation of premalignant and senescent-positive
lung lesions in favor of malignant and senescent-negative adenocarcinomas.
These investigations propose the novel concept that targeting K-Ras-dependent signaling that bypasses OIS
through downregulaton of caveolin-1 expression, which will be identified in this proposal, is an alternative and
better therapeutic option then targeting K-Ras itself: it will allow the selective inhibition of pro-tumorigenic K-
Ras signaling while rescuing pro-senescent K-Ras pathways. This new information has the potential to directly
impact the development of novel therapeutic interventions to prevent the progression to lung
adenocarcinomas.
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会议论文
Mechanisms that control the progression from premalignant lesions to adenocarcinomas in the lung
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批准号:9305499
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项目类别:
-
资助金额:$31.03万
-
财政年份:2017
-
负责人:FERRUCCIO GALBIATI
-
依托单位:
Mechanisms that control the progression from premalignant lesions to adenocarcinomas in the lung
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批准号:9899946
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项目类别:
-
资助金额:$31.3万
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财政年份:2017
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负责人:FERRUCCIO GALBIATI
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依托单位:
Caveolin-1-mediated senescence, chronic inflammation and age-related lung disease
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批准号:9279206
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项目类别:
-
资助金额:$38.5万
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财政年份:2015
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负责人:FERRUCCIO GALBIATI
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依托单位:
Caveolin-1-mediated senescence, chronic inflammation and age-related lung disease
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批准号:9059176
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项目类别:
-
资助金额:$38.5万
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财政年份:2015
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负责人:FERRUCCIO GALBIATI
-
依托单位:
Caveolin-1-mediated senescence, chronic inflammation and age-related lung disease
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批准号:8903586
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项目类别:
-
资助金额:$38.5万
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财政年份:2014
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负责人:FERRUCCIO GALBIATI
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依托单位:
Caveolin 1: a novel modulator of the PP2A/ATM/p53 pathway
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批准号:8507585
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项目类别:
-
资助金额:$27.47万
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财政年份:2009
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负责人:FERRUCCIO GALBIATI
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依托单位:
Caveolin 1: a novel modulator of the PP2A/ATM/p53 pathway
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批准号:8114097
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项目类别:
-
资助金额:$29.07万
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财政年份:2009
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负责人:FERRUCCIO GALBIATI
-
依托单位:
Caveolin 1: a novel modulator of the PP2A/ATM/p53 pathway
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批准号:8301580
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项目类别:
-
资助金额:$29.07万
-
财政年份:2009
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负责人:FERRUCCIO GALBIATI
-
依托单位:
Caveolin 1: a novel modulator of the PP2A/ATM/p53 pathway
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批准号:7903303
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项目类别:
-
资助金额:$30.25万
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财政年份:2009
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负责人:FERRUCCIO GALBIATI
-
依托单位:
Caveolin 1: a novel modulator of the PP2A/ATM/p53 pathway
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批准号:7574065
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项目类别:
-
资助金额:$30.55万
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财政年份:2009
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负责人:FERRUCCIO GALBIATI
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依托单位:
Role of Caveolin-1 in Cellular Senescence and Aging
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批准号:7569471
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项目类别:
-
资助金额:$24.43万
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财政年份:2005
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负责人:FERRUCCIO GALBIATI
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依托单位:
Role of Caveolin-1 in Cellular Senescence and Aging
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批准号:7364641
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项目类别:
-
资助金额:$24.45万
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财政年份:2005
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负责人:FERRUCCIO GALBIATI
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依托单位:
Role of Caveolin-1 in Cellular Senescence and Aging
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批准号:6999304
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项目类别:
-
资助金额:$25.71万
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财政年份:2005
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负责人:FERRUCCIO GALBIATI
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依托单位:
Role of Caveolin-1 in Cellular Senescence and Aging
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批准号:7173379
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项目类别:
-
资助金额:$24.96万
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财政年份:2005
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负责人:FERRUCCIO GALBIATI
-
依托单位:
Role of Caveolin-1 in Cellular Senescence and Aging
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批准号:6873200
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项目类别:
-
资助金额:$26.34万
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财政年份:2005
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负责人:FERRUCCIO GALBIATI
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依托单位:
海外基金