Aberrant Glycogen in Lung Adenocarcinoma Tumorigenesis
Aberrant Glycogen in Lung Adenocarcinoma Tumorigenesis
批准号:
10518440
负责人:
Matthew S. Gentry
金额:
$5.25万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
已结题
起止时间:
2022-07-01 至 2022-10-31
关键词:
5&apos-AMP-activated protein kinaseAffinityApoptosisAutomobile DrivingBindingBiochemicalBiochemistryBiological AssayBiologyBiophysicsCancer BiologyCancer EtiologyCancer PatientCarbonCell CycleCell LineClinicalCoupledDataDevelopmentDiagnosisEtiologyFoundationsFutureGeneticGlucoseGlycogenGoalsHistologicIn SituKRASG12DKentuckyKnock-outKnowledgeLipidsLongitudinal StudiesLungLung AdenocarcinomaLung NeoplasmsMalignant neoplasm of lungMediatingMetabolicMetabolismMetastatic Neoplasm to Lymph NodesMethodologyMethodsModalityModelingMolecularMonitorMusMutateMutationNCI-Designated Cancer CenterNon-Small-Cell Lung CarcinomaNucleotidesOncogenicOperative Surgical ProceduresOrganoidsPathogenicityPatientsPhenotypePhosphoric Monoester HydrolasesPhosphorylationPhysiologicalPopulationPrecision therapeuticsPropertyProtein KinaseProteinsQuality of lifeRadiationReportingResolutionRoleSTK11 geneSamplingSignal TransductionSquamous Cell Lung CarcinomaStagingStructure of parenchyma of lungTP53 geneTechnologyTestingTissuesTransgenic MiceTumor BiologyTumor PathologyUniversitiesanticancer researchbasechemotherapycohortfatty acid oxidationgenetically modified cellsglucose metabolismin vivoknowledge basemass spectrometric imagingmetabolomicsmortalitymouse modelmutantnovelpersonalized medicinepre-clinicalpreventstable isotopetumortumor metabolismtumor progressiontumorigenesis
中文摘要
摘要:
肺腺癌(LUAD)是肺癌的主要组织学亚型,也是肺癌的主要原因。
全球癌症相关死亡率。对于大量 LUAD 患者来说,唯一的治疗选择
可用的是传统的多药化疗结合手术和/或放疗。对于这些患者来说,
5年生存率仍然低得令人失望。驱动 LUAD 增殖的其他分子机制
和肿瘤发生仍然是肺癌研究中的一个关键知识空白,也是肺癌研究的一个主要障碍
个性化疗法的发展。最近的报告,包括我们自己的报告,揭示了糖原在以下方面的关键作用:
肺部肿瘤进展。在这些基础研究的基础上,我们开发了强大且精确的
使用质谱成像以 50 µm 空间分辨率原位可视化糖原的技术
与以前的方法相比,灵敏度提高了 1,000 倍。使用这项技术,我们定义了
肯塔基大学 NCI 指定癌症中心治疗的 122 名 NSCLC 患者的糖原水平。
我们的初步数据表明:1)在 LUAD 中观察到糖原显着升高,而在
正常肺组织。 2) 糖原升高是 LUAD 组织特异性标志,在肺中未观察到
鳞状细胞癌。 3) LUAD-糖原结构独特,磷酸化程度增加,
分支。 4) 这种 LUAD 表型与糖原磷酸酶中蛋白质的显着降低相关
拉福林。引人注目的是,模型肺细胞系和 KrasG12D/p53-/- LUAD 小鼠模型中的 laforin 敲除驱动:1)
糖原过度磷酸化,2) 与主代谢调节剂 AMP 激活的亲和力增加
蛋白激酶 (AMPK),3) 降低 AMPK 活性,4) 加速肿瘤增殖和进展。
我们假设结构独特的 LUAD 糖原是 LUAD 代谢的关键组成部分,
增殖和进展。本研究的总体目标是确定 LUAD-糖原的病因学
癌症代谢和肿瘤进展。为了实现这一目标,我们将: 定义 LUAD-糖原临床
课程及其与 AMPK 的相互作用(目标 1)。然后,我们将定义 LUAD-糖原在
通过 AMPK 进行细胞代谢(目标 2)。最后,我们将确定 LUAD-糖原在肿瘤中的作用
体内进展和早期转化(Aim3)。该提案建立在令人兴奋且严格的初步基础上
数据并提出了一种综合方法来定义过量糖原利用的独特 LUAD 标志
稳健、互补且最先进的方法,例如质谱成像、蛋白质和
糖原生物化学和靶向代谢组学。该提案的显着发现将显着
推进有关糖原在 LUAD 生物学和进展中的作用的知识库,并推动
发现可用于仅符合资格的 LUAD 人群的个性化疗法
常规化疗。
英文摘要
Abstract:
Lung adenocarcinoma (LUAD) is the major histological subtype of lung cancer and the leading cause of
cancer-related mortalities worldwide. For a substantial number of LUAD patients, the only treatment options
available are traditional multi-agent chemotherapy coupled with surgery and/or radiation. For these patients,
the 5-year survival remains disappointingly low. Additional molecular mechanisms driving LUAD proliferation
and tumorigenesis remain a critical knowledge gap in lung cancer research, and a major barrier for the
development of personalized therapies. Recent reports, including our own, reveal critical roles for glycogen in
lung tumor progression. Building on these foundational studies, we developed a robust and precision
technology to visualize glycogen in situ with 50 µm spatial resolution using mass spectrometry imaging that
provides 1,000x increased sensitivity compared to previous methods. Using this technology, we defined
glycogen levels in 122 NSCLC patients treated at the University of Kentucky’s NCI Designated Cancer Center.
Our preliminary data demonstrate that: 1) significantly elevated glycogen is observed in LUAD and not in
normal lung tissue. 2) Elevated glycogen is a LUAD tissue-specific hallmark and is not observed in lung
squamous cell carcinoma. 3) LUAD-glycogen is structurally unique with increased phosphorylation and
branching. 4) This LUAD phenotype correlated with marked protein decreases in the glycogen phosphatase
laforin. Strikingly, laforin knockout in model lung cell lines and the KrasG12D/p53-/- LUAD mouse model drives: 1)
glycogen hyper-phosphorylation, 2) increased affinity with the master metabolic regulator AMP-activated
protein kinase (AMPK), 3) decreased AMPK activity, and 4) accelerated tumor proliferation and progression.
We hypothesize that the structurally unique LUAD-glycogen is a critical component of LUAD metabolism,
proliferation, and progression. The overall objective of this study is to define the etiology of LUAD-glycogen on
both cancer metabolism and tumor progression. To achieve this, we will: Define the LUAD-glycogen clinical
course and its interaction with AMPK (Aim 1). Then, we will define the signaling role of LUAD-glycogen in
cellular metabolism through AMPK (Aim 2). Finally, we will establish the role of LUAD-glycogen in tumor
progression and early transformation in vivo (Aim3). This proposal builds on exciting and rigorous preliminary
data and presents an integrated approach to define this unique LUAD hallmark of excess glycogen utilizing
robust, complementary, and state-of-the-art methodologies such as mass spectrometry imaging, protein and
glycogen biochemistry, and targeted metabolomics. The salient findings from this proposal will significantly
advance the knowledge base regarding the roles of glycogen in LUAD biology and progression and drive the
discovery of personalized therapies that can be leveraged for the LUAD population that only qualify for
conventional chemotherapy.
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会议论文
Aberrant Glycogen in Lung Adenocarcinoma Tumorigenesis
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批准号:10644000
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项目类别:
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资助金额:$53.36万
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财政年份:2022
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负责人:Matthew S. Gentry
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依托单位:
Aberrant Glycogen in Lung Adenocarcinoma Tumorigenesis
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批准号:10748000
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财政年份:2022
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批准号:10285469
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资助金额:$0.19万
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财政年份:2021
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负责人:Matthew S. Gentry
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依托单位:
Brain Glycogen - Metabolism, Mechanisms, and Therapeutic Potential
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批准号:10610572
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财政年份:2020
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批准号:10786602
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项目类别:
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资助金额:$7.43万
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财政年份:2020
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负责人:Matthew S. Gentry
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依托单位:
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批准号:10401225
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项目类别:
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资助金额:$38.25万
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财政年份:2020
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批准号:10405662
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资助金额:$114.75万
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财政年份:2020
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负责人:Matthew S. Gentry
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依托单位:
Brain Glycogen - Metabolism, Mechanisms, and Therapeutic Potential
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批准号:10159325
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项目类别:
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资助金额:$114.75万
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财政年份:2020
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负责人:Matthew S. Gentry
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批准号:10730778
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资助金额:$106.3万
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财政年份:2020
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Lafora Epilepsy - Basic mechanisms to therapy
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资助金额:$186.51万
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依托单位:
Lafora Epilepsy - Basic mechanisms to therapy
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批准号:9309102
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资助金额:$172.25万
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财政年份:2016
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Lafora Epilepsy - Basic mechanisms to therapy
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资助金额:$178.45万
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财政年份:2016
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Regulation, signaling, and dynamics of glucan phosphatases.
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Regulation, signaling, and dynamics of glucan phosphatases.
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Regulation, signaling, and dynamics of glucan phosphatases
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财政年份:2010
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依托单位:
THE CONNECTION BETWEEN LAFORA DISEASE AND OTHER POLYGLUCOSAN BODY DISEASES
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批准号:8168251
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项目类别:
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资助金额:$22.75万
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财政年份:2010
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负责人:Matthew S. Gentry
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依托单位:
Regulation, signaling, and dynamics of glucan phosphatases.
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批准号:8642327
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海外基金