Exosome-mediated mechanisms of metastatic disease in non-small cell lung cancer
Exosome-mediated mechanisms of metastatic disease in non-small cell lung cancer
批准号:
10513810
负责人:
Steven M. Dubinett
金额:
$0.0万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-10-01 至 2024-09-30
关键词:
AntibodiesBehaviorBiologyCD8-Positive T-LymphocytesCancer EtiologyCarcinomaCause of DeathCell CommunicationCell physiologyCellsCessation of lifeClinicalClustered Regularly Interspaced Short Palindromic RepeatsDataData SetDetectionDevelopmentDiseaseDisease ProgressionDisseminated Malignant NeoplasmEarly InterventionEpithelial CellsEpitheliumEventFundingHumanImmunofluorescence ImmunologicImmunosuppressionIn VitroInterferon Type IIKnock-outLungMalignant NeoplasmsMalignant Pleural EffusionMalignant neoplasm of lungMediatingMediatorMesenchymalMovementMutationNeoplasm MetastasisNew AgentsNon-Small-Cell Lung CarcinomaNormal CellOperative Surgical ProceduresParacrine CommunicationPatientsPhenotypePremalignant CellProcessProteinsProteomicsReportingResearchResourcesTimeUnited States Department of Veterans AffairsVeteransWestern Blottingairway epitheliumbiobankbiomarker discoverybronchial epitheliumcancer cellcell motilityconstrictioncytokineexosomein vivoindividual patientinnovationinsightlung cancer celllung lesionmiRNA expression profilingmigrationperipheral bloodphysical propertypremalignantpreventprogrammed cell death ligand 1programmed cell death protein 1transcriptomic profiling
中文摘要
肺癌是美国退伍军人癌症死亡的首要原因,转移性疾病占压倒性多数
最主要的死因。根据我们的初步发现,我们假设外显体起源于
高度活动的癌前细胞可以通过旁分泌将转移表型转移到邻近的正常细胞
发信号。在当前退伍军人事务部(VA)功绩审查资助期,我们确定并选择了
观察到的高度迁移的癌前呼吸道上皮细胞亚群
微尺度收缩的速率高达对照未选择细胞的100倍。这些高度迁移的细胞
在体内表现出增强的转移行为。我们从这些高度敏感的生物中分离并鉴定了外切体
移行性癌前病变上皮细胞以及恶性胸腔积液(MPE)来源
转移性癌细胞。在癌前疾病和转移性疾病的环境中,包含独特的
基因组特征将转移表型转移到非运动性细胞。从这些签名中,我们有
确定了调节转移行为和免疫抑制转移的潜在候选者。至
为了方便对转移疾病的研究,我们将利用我们的MPE-生物库来分离和
来自个体患者MPE来源的转移性肺癌细胞的特征。虽然外显体是已知的
为了在导致癌症转移的细胞相互作用中充当功能介体,这将是第一次
全面研究,以充分描述这些事件背后的机制在肺
癌前迁移,以及在MPE转移细胞的背景下。为了刻画和描述
了解这一过程在调节促进迁徙能力和
癌前病变和转移性肺癌细胞的免疫抑制我们将:1)确定
外切体通过表征非小细胞肺癌疾病谱来推动疾病进展
来自癌前和转移癌细胞的胞外物,2)决定了肿瘤的机制
外切体依赖促进上皮细胞间充质转化和迁移能力的研究
和肺癌细胞,以及3)确定外切体依赖的免疫抑制的机制。而当
据报道,外切体在导致癌症的细胞相互作用中起着功能中介作用。
转移,这将是第一个全面的研究,以充分表征潜在的机制充分
在肺癌前转移和转移性肺癌的背景下,疾病的范围都是如此。
在癌前病变和转移的背景下,外切体介导的转移调控的研究是独一无二的
将有助于定义隐匿性转移的生物学,为平行转移现象提供洞察力
进展,增加发现生物标记物的可能性,并为肺癌的阻断提供靶点。
英文摘要
Lung cancer is the leading cause of cancer death among US Veterans, and metastatic disease is overwhelmingly
the predominant cause of death. Based on our preliminary findings, we hypothesize that exosomes derived from
highly motile premalignant cells can transfer metastatic phenotypes to neighboring normal cells via paracrine
signaling. In the current Veteran Affairs (VA) Merit Review funding period, we identified and selected a
subpopulation of highly migratory premalignant airway epithelial cells that were observed to migrate through
microscale constrictions at up to 100-fold the rate of the control unselected cells. These highly migratory cells
demonstrate enhanced metastatic behavior in vivo. We isolated and characterized exosomes from these highly
migratory premalignant human airway epithelial cells, as well as, malignant pleural effusion (MPE)-derived
metastatic cancer cells. In both settings of premalignancy and metastatic disease, exosomes containing unique
omic signatures transferred the metastatic phenotype to non-motile cells. From these signatures, we have
identified potential candidates mediating the transfer of metastatic behavior and immunosuppression. To
facilitate the study of metastatic disease, we will utilize our MPE-biobank for exosome isolation and
characterization from individual patient's MPE-derived metastatic lung cancer cells. While exosomes are known
to serve as functional mediators in cell interaction leading to cancer metastasis, this will be the first
comprehensive study to fully characterize the mechanisms underlying these events in the context of pulmonary
premalignant migration, as well as, in the context of metastatic cells from MPEs. In order to characterize and
understand the mechanisms of this process in regulating the promotion of migratory capacity and
immunosuppression in premalignant and metastatic lung cancer cells we will: 1) Determine the capacity of
exosomes to drive disease progression across the spectrum of disease in NSCLC by characterizing the
exosomal cargo derived from premalignant and metastatic cancer cells, 2) Determine the mechanisms of
exosome-dependent promotion of epithelial mesenchymal transition (EMT) and migratory capacity of epithelial
and lung cancer cells and, 3) determine the mechanisms of exosome-dependent immune suppression. While
exosomes have been reported to serve as functional mediators in cellular interaction leading to cancer
metastasis, this will be the first comprehensive study to fully characterize the mechanisms underlying the full
spectrum of disease, both in the context of pulmonary premalignant migration as well as metastatic lung cancer.
This study of exosome mediated metastatic-modulation in the context of premalignancy and metastasis is unique
and will help define the biology of occult metastasis, provide insights into the phenomenon of parallel
progression, increase the possibility of biomarker discovery and provide targets for lung cancer interception.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Early detection of metastatic disease in US Veterans following surgery for early stage lung cancer
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批准号:10426073
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项目类别:
-
资助金额:$0.0万
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财政年份:2020
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负责人:Steven M. Dubinett
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依托单位:
Exosome-mediated mechanisms of metastatic disease in non-small cell lung cancer
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批准号:10293525
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项目类别:
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资助金额:$0.0万
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财政年份:2020
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负责人:Steven M. Dubinett
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Exosome-mediated mechanisms of metastatic disease in non-small cell lung cancer
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批准号:9784401
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Novel Computation Methods for the Analysis of Cell-Free DNA Sequence Data
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批准号:10238894
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项目类别:
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资助金额:$55.22万
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负责人:Steven M. Dubinett
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依托单位:
Novel Computation Methods for the Analysis of Cell-Free DNA Sequence Data
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批准号:10004012
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资助金额:$55.22万
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财政年份:2019
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依托单位:
The Lung PCA: A Multi-Dimensional Atlas of Pulmonary Premalignancy
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批准号:10203247
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项目类别:
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资助金额:$15.99万
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财政年份:2018
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负责人:Steven M. Dubinett
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依托单位:
The Lung PCA: A Multi-Dimensional Atlas of Pulmonary Premalignancy
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批准号:10441645
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项目类别:
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资助金额:$10.0万
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财政年份:2018
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负责人:Steven M. Dubinett
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依托单位:
Molecular, Cellular, and Tissue Characterization Unit
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批准号:9627277
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项目类别:
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资助金额:$110.1万
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财政年份:2018
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负责人:Steven M. Dubinett
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依托单位:
UCLA Clinical Translational Science Institute
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批准号:10200543
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资助金额:$23.45万
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财政年份:2016
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负责人:Steven M. Dubinett
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依托单位:
ConProject-001
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批准号:10311408
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资助金额:$32.67万
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负责人:Steven M. Dubinett
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依托单位:
UCLA Clinical Translational Science Institute
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批准号:10401701
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项目类别:
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资助金额:$627.15万
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财政年份:2016
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资助金额:$1478.8万
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Clinically Actionable Neoantigens in Non-Small Cell Lung Cancer
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负责人:Steven M. Dubinett
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Intratumoral genetic therapy for lung cancer
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批准号:8461073
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资助金额:$0.0万
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财政年份:2012
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负责人:Steven M. Dubinett
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依托单位:
Intratumoral genetic therapy for lung cancer
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批准号:7934435
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项目类别:
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资助金额:$0.0万
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财政年份:2012
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负责人:Steven M. Dubinett
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依托单位:
Clinically Actionable Neoantigens in Non-Small Cell Lung Cancer
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批准号:9348557
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项目类别:
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资助金额:$0.0万
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财政年份:2012
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依托单位:
Intratumoral genetic therapy for lung cancer
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批准号:8698360
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资助金额:$0.0万
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依托单位:
Intratumoral genetic therapy for lung cancer
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批准号:8967131
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资助金额:$0.0万
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财政年份:2012
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负责人:Steven M. Dubinett
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依托单位:
UCLA Clinical and Translational Science Institute
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批准号:8270466
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资助金额:$81.24万
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财政年份:2011
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负责人:Steven M. Dubinett
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依托单位:
UCLA Clinical and Translational Science Institute
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批准号:8634157
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项目类别:
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资助金额:$77.26万
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财政年份:2011
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负责人:Steven M. Dubinett
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依托单位:
国内基金
海外基金
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批准号:--
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项目类别:外国学者研究基金项目
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负责人:YU BYUNGJUN
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依托单位:
Incentive and governance schenism study of corporate green washing behavior in China: Based on an integiated view of econfiguration of environmental authority and decoupling logic
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资助金额:--
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批准年份:2024
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负责人:YU BYUNGJUN
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依托单位: