A novel lineage pathway controls metabolic adaptation by metastatic lung cancers
一种新的谱系途径控制转移性肺癌的代谢适应
基本信息
- 批准号:9182876
- 负责人:
- 金额:$ 38.03万
- 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:2014-12-15 至 2019-11-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdenocarcinoma CellAdjuvant TherapyAffectAggressive Clinical CourseAlpha CellAlveolarAmino AcidsAmino Acids ActivationAnabolismAnoikisApoptosisAsparagineAspartate-Ammonia LigaseAttenuatedBioenergeticsBiogenesisBioinformaticsBiologicalBiological ProcessBiological Response Modifier TherapyBiologyBlood CirculationCancer PatientCatabolismCatalogingCatalogsCell LineageCell SurvivalCell modelCellsCellular Metabolic ProcessCessation of lifeClinicalCompetenceConsumptionCoupledDevelopmentDiseaseDistantEnzymesEpithelialExposure toExtracellular MatrixGene DeliveryGenesGeneticGenetic TranscriptionGenetically Engineered MouseGenomicsHomeostasisHumanHuman GenomeHypoxiaLinkLungLung AdenocarcinomaLung CapacityMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of thoraxMetabolicMetabolic ControlMetabolic PathwayMetabolic stressModelingMolecularMorphogenesisMutationNeoplasm MetastasisNutrientOrganOutcomePathway interactionsPatientsPhosphotransferasesPhysiologicalRelapseRepressionResectedResidual NeoplasmRiskRoleSerineSourceStarvationStressTP53 geneTherapeuticTissuesTranscription CoactivatorTransfer RNAXenograft ModelXenograft procedureamino acid metabolismaminoacid biosynthesisbiological adaptation to stressbiological heterogeneitycancer cellcancer subtypescell typedetection of nutrientenzyme biosynthesisextracellularhuman tissuein vivoinnovationinsightinterdisciplinary approachknock-downloss of functionmetabolomicsmouse modelnoveloutcome forecastprogramsprospectiveproteostasispublic health relevanceresponsesensortherapeutic targettherapy resistanttranscription factortumortumor microenvironmenttumor progressiontumorigenesis
项目摘要
DESCRIPTION (provided by applicant): Thoracic malignancies account for the majority of cancer-related deaths. The most frequent lung cancer subtype is lung adenocarcinoma (LuAd), which displays remarkable biological heterogeneity and poor prognosis. A subset of LuAds rapidly diverge in their differentiation states, correlating with therapeutic resistance and metastatic relapse. Despite recent advances in cataloguing the genome of human lung cancers, the molecular and biological determinants of LuAd metastasis remain poorly understood. By employing innovative genomics and experimental approaches, we uncovered a molecular link between LuAd metastasis, airway epithelial specification, and metabolic reprogramming. In particular, we discovered a novel pathway that suppresses the metastatic proclivity of LuAd cells through the lineage transcription factor HOPX. HOPX not only directs alveolar differentiation, but also constrains a metabolic stress response by inhibiting the activity of the nutrient sensing kinase GCN2 (general control nonrepressed 2) and its downstream control of amino acid biosynthesis. We hypothesize that the suppression of HOPX primes high-grade LuAd cells to activate a metabolic pathway that pre-conditions them for subsequent metastasis. We refer to this pathway as a Lineage directed Adaptive Stress Response (LASR) and predict that it will increase the adaptive capacity of LuAd cells for various metastatic niches. Our hypothesis will be studied by integrating bioinformatics, molecular, metabolomic, and biological approaches. In Aim 1, we will determine the transcriptional mechanism by which the LASR is activated in LuAds and ascertain its correlation with clinical outcome in human biospecimens. In Aim 2, we will determine the function of key LASR enzymatic effectors in metastatic LuAd cells, by modeling conditions of metabolic and microenvironmental stress in circulation and the extracellular matrix. We will also perform a metabolic flux analysis of asparagine and serine, two amino acids whose catabolism is predicted to be required for LuAd cell dissemination and their emergence from dormancy. In Aim 3, we will characterize the requirement for the LASR during LuAd differentiation, progression, and metastatic colonization in vivo. To this end, we will employ spatio-temporally controlled gain or loss of function approaches, using our established xenograft model of human LuAd as well as a novel targeting approach in a complementary genetically engineered mouse model. Our findings reveal how epithelial metabolic adaptation is under the direct control of developmental programs in the lungs. The deregulation of this novel pathway also provides a cogent mechanism for the elevated risk of certain early stage lung cancers to metastasize. Finally, our proposal will generate significant insight as to how prospective therapeutics directed against amino acid metabolism and proteostasis can be effectively harnessed for adjuvant therapy and/or the treatment of late stage metastasis.
描述(由申请方提供):胸部恶性肿瘤占癌症相关死亡的大多数。最常见的肺癌亚型是肺腺癌(LuAd),其表现出显著的生物学异质性和不良预后。LuAd的一个子集在其分化状态中迅速分化,与治疗抗性和转移性复发相关。尽管最近在人类肺癌基因组编目方面取得了进展,但LuAd转移的分子和生物学决定因素仍然知之甚少。通过采用创新的基因组学和实验方法,我们发现了LuAd转移,气道上皮特化和代谢重编程之间的分子联系。特别是,我们发现了一种新的途径,通过谱系转录因子HOPX抑制LuAd细胞的转移倾向。HOPX不仅指导肺泡分化,而且通过抑制营养传感激酶GCN 2(一般控制非抑制2)及其下游氨基酸生物合成控制的活性来抑制代谢应激反应。我们假设HOPX的抑制引发高级别LuAd细胞激活代谢途径,为随后的转移做好准备。我们将该途径称为谱系定向适应性应激反应(LASR),并预测它将增加LuAd细胞对各种转移性小生境的适应能力。我们的假设将通过整合生物信息学,分子,代谢组学和生物学方法进行研究。在目标1中,我们将确定LASR在LuAds中被激活的转录机制,并确定其与人类生物标本中临床结果的相关性。在目标2中,我们将通过模拟循环和细胞外基质中的代谢和微环境应激条件来确定转移性LuAd细胞中关键LASR酶效应子的功能。我们还将进行天冬酰胺和丝氨酸的代谢通量分析,这两种氨基酸的催化剂被预测为LuAd细胞传播和它们从休眠中出现所需的。在目标3中,我们将表征在体内LuAd分化、进展和转移性定殖期间对LASR的需求。为此,我们将采用时空控制的功能获得或丧失方法,使用我们建立的人LuAd异种移植模型以及互补基因工程小鼠模型中的新靶向方法。我们的研究结果揭示了上皮细胞的代谢适应是如何在肺部发育程序的直接控制下。这种新途径的失调也为某些早期肺癌转移的风险升高提供了一种令人信服的机制。最后,我们的建议将产生重要的见解,如何针对氨基酸代谢和蛋白质代谢抑制的前瞻性疗法可以有效地利用辅助治疗和/或晚期转移的治疗。
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)
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 }}
Don X Nguyen其他文献
Don X Nguyen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('Don X Nguyen', 18)}}的其他基金
Uncovering the Biology of Resistance to Tyrosine Kinase Inhibitors in EGFR Mutant Lung Cancer Patient-Derived Models.
揭示 EGFR 突变肺癌患者衍生模型中酪氨酸激酶抑制剂耐药性的生物学。
- 批准号:
9920134 - 财政年份:2019
- 资助金额:
$ 38.03万 - 项目类别:
Uncovering the Biology of Resistance to Tyrosine Kinase Inhibitors in EGFR Mutant Lung Cancer Patient-Derived Models.
揭示 EGFR 突变肺癌患者衍生模型中酪氨酸激酶抑制剂耐药性的生物学。
- 批准号:
10376749 - 财政年份:2019
- 资助金额:
$ 38.03万 - 项目类别:
Uncovering the Biology of Resistance to Tyrosine Kinase Inhibitors in EGFR Mutant Lung Cancer Patient-Derived Models.
揭示 EGFR 突变肺癌患者衍生模型中酪氨酸激酶抑制剂耐药性的生物学。
- 批准号:
10616672 - 财政年份:2019
- 资助金额:
$ 38.03万 - 项目类别:
Project 3: Identifying and targeting mediators of CNS metastasis from lung cancer
项目3:识别和靶向肺癌中枢神经系统转移的介质
- 批准号:
10203856 - 财政年份:2015
- 资助金额:
$ 38.03万 - 项目类别:
A novel lineage pathway controls metabolic adaptation by metastatic lung cancers
一种新的谱系途径控制转移性肺癌的代谢适应
- 批准号:
8984877 - 财政年份:2014
- 资助金额:
$ 38.03万 - 项目类别:
Epigenetic modulation of lung cancer metastasis by a novel long intergenic RNA
新型长基因间RNA对肺癌转移的表观遗传调节
- 批准号:
8900254 - 财政年份:2014
- 资助金额:
$ 38.03万 - 项目类别:
A Novel Lineage Specific Metastasis Suppressor Pathway in Lung Cancer
肺癌中一种新的谱系特异性转移抑制途径
- 批准号:
8681391 - 财政年份:2012
- 资助金额:
$ 38.03万 - 项目类别:
A NOVEL LINEAGE SPECIFIC METASTASIS PATHWAY IN LUNG CANCER
肺癌中一种新的谱系特异性转移途径
- 批准号:
10066312 - 财政年份:2012
- 资助金额:
$ 38.03万 - 项目类别:
A NOVEL LINEAGE SPECIFIC METASTASIS PATHWAY IN LUNG CANCER
肺癌中一种新的谱系特异性转移途径
- 批准号:
9884455 - 财政年份:2012
- 资助金额:
$ 38.03万 - 项目类别:
A Novel Lineage Specific Metastasis Suppressor Pathway in Lung Cancer
肺癌中一种新的谱系特异性转移抑制途径
- 批准号:
8436668 - 财政年份:2012
- 资助金额:
$ 38.03万 - 项目类别:
相似海外基金
Assessing The Impact of Heparanase and NDST2 Expression on Non-Small Cell Lung Adenocarcinoma Cell Motility
评估乙酰肝素酶和 NDST2 表达对非小细胞肺腺癌细胞运动的影响
- 批准号:
449570 - 财政年份:2020
- 资助金额:
$ 38.03万 - 项目类别:
Studentship Programs
Analysis of cancer metastasis and invasion mechanism using a new lung adenocarcinoma cell line.
使用新的肺腺癌细胞系分析癌症转移和侵袭机制。
- 批准号:
16K10689 - 财政年份:2016
- 资助金额:
$ 38.03万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Acquisition strategy of tumor-specific markers using established micropapillary pattern pulmonary adenocarcinoma cell line
使用已建立的微乳头模式肺腺癌细胞系获取肿瘤特异性标志物的策略
- 批准号:
26460441 - 财政年份:2014
- 资助金额:
$ 38.03万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The antibetic drug metformin inhibits esophageal adenocarcinoma cell proliferation in vitro and in vivo.
抗生素药物二甲双胍在体外和体内抑制食管腺癌细胞增殖。
- 批准号:
25860540 - 财政年份:2013
- 资助金额:
$ 38.03万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
The cell permeable peptide inhibits pancreatic ductal adenocarcinoma cell proliferations and can be used as the molecular targeting dru
细胞通透肽抑制胰腺导管腺癌细胞增殖,可作为分子靶向药物
- 批准号:
25461969 - 财政年份:2013
- 资助金额:
$ 38.03万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Basic Research for elucidation of chemo-resistance in mucinous adenocarcinoma cell.
阐明粘液腺癌细胞化疗耐药性的基础研究。
- 批准号:
22791532 - 财政年份:2010
- 资助金额:
$ 38.03万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
TAS::75 0849::TAS IN THIS PHASE I SBIR THE BREAST CANCER ADENOCARCINOMA CELL LI
TAS::75 0849::TAS 在这一阶段 I SBIR 乳腺癌腺癌细胞 LI
- 批准号:
8164743 - 财政年份:2010
- 资助金额:
$ 38.03万 - 项目类别:
Role of Endothelin-1 in osteoblastic bone metastasis produced by a human lung adenocarcinoma cell line
Endothelin-1 在人肺腺癌细胞系产生的成骨细胞骨转移中的作用
- 批准号:
19790127 - 财政年份:2007
- 资助金额:
$ 38.03万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
CONNEXIN 43 EXPRESSION IN ADENOCARCINOMA CELL LINE
连接蛋白 43 在腺癌细胞系中的表达
- 批准号:
6972483 - 财政年份:2004
- 资助金额:
$ 38.03万 - 项目类别:
The mechanisms of highly metastetic capasity in highly metastatic subpopulations of lung adenocarcinoma cell line and these clinical applications
肺腺癌细胞系高转移亚群的高转移能力机制及临床应用
- 批准号:
15590831 - 财政年份:2003
- 资助金额:
$ 38.03万 - 项目类别:
Grant-in-Aid for Scientific Research (C)