The Macropinosome: Uncovering the Molecular Anatomy of an Oncogene-driven Organelle
The Macropinosome: Uncovering the Molecular Anatomy of an Oncogene-driven Organelle
批准号:
10153719
负责人:
Cosimo Commisso
金额:
$22.79万
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:
2020-05-01 至 2023-04-30
关键词:
ActinsAmino AcidsAnabolismAnatomyArchitectureBackBiological AssayBiological MarkersCancer BiologyCarbonCatabolic ProcessCell membraneClinicalDevelopmentEncapsulatedEndocytic VesicleEndocytosisEvaluationEventExtracellular ProteinFosteringGoalsGrowthKRAS oncogenesisKRAS2 geneLiquid substanceLysosomesMalignant NeoplasmsMediatingMembraneMetabolicMethodologyModelingMolecularMutationNanotechnologyNutrientOncogenesOncogenicOrganellesOutcomePancreatic Ductal AdenocarcinomaPathway interactionsPatientsPhasePositioning AttributeProcessProductionProliferatingPropertyProteinsProteomeProteomicsRegulationRoleRouteSignal TransductionTechniquesTechnologyTherapeuticbasecancer cellcancer therapyexperimental studyferriteinnovationinsightknock-downmetabolic fitnessmutantnanoparticleneoplastic cellnovelpancreatic ductal adenocarcinoma cellpancreatic ductal adenocarcinoma modelprecision medicinetumortumor metabolismtumor microenvironmentuptake
中文摘要
项目摘要
作为癌症中发生的代谢重编程的一个不可或缺的方面,致癌KRAS突变驱动
刺激巨胞饮作用,一种介导非选择性液相摄取的内吞作用。使用
KRAS驱动的胰腺导管腺癌(PDAC)模型,我们首次证明,
巨胞饮作用在肿瘤细胞中起营养获取途径的作用。巨胞饮作用触发
细胞外蛋白通过称为巨胞饮体的离散内吞囊泡内化。传入
蛋白质货物是溶酶体依赖性降解的目标,引起氨基酸的细胞内释放。
这些蛋白质衍生的氨基酸通过贡献于细胞内氨基酸库来支持代谢适应性,
以及中心碳代谢物的生物合成。这样,巨胞饮作用代表了一种新的
肿瘤细胞用来在肿瘤的营养不良条件下生存的氨基酸供应途径
微环境虽然在癌症中驱动巨胞饮的信号转导事件的原理
虽然大胞饮体已经出现,但它本身的详细图像还没有。借助纳米技术,我们
已经开发了从PDAC细胞中分离大胞饮体的纯级分的方法。具有
纯化大胞饮体的能力,我们现在处于独特的地位,受益于大规模蛋白质组学,
可以提供这个重要细胞器的全貌。通过阐明KRAS驱动的
通过对巨胞饮体的研究,我们将进一步了解巨胞饮在癌症中的调节和功能。
此外,更清楚地了解大胞饮体将使我们更好地利用这一途径
治疗并为患者带来突破。
英文摘要
PROJECT SUMMARY
As an integral aspect of the metabolic reprogramming that occurs in cancer, oncogenic KRAS mutations drive
the stimulation of macropinocytosis, a type of endocytosis that mediates nonselective fluid-phase uptake. Using
KRAS-driven models of pancreatic ductal adenocarcinoma (PDAC), we were the first to demonstrate that
macropinocytosis functions in tumor cells as a nutrient acquisition pathway. Macropinocytosis triggers the
internalization of extracellular proteins via discrete endocytic vesicles called macropinosomes. The incoming
protein cargo is targeted for lysosome-dependent degradation, causing the intracellular release of amino acids.
These protein-derived amino acids support metabolic fitness by contributing to the intracellular amino acid pools,
as well as to the biosynthesis of central carbon metabolites. In this way, macropinocytosis represents a novel
amino acid supply route that tumor cells use to survive the nutrient-poor conditions of the tumor
microenvironment. While the tenets of the signal transduction events that drive macropinocytosis in cancer have
emerged, a detailed picture of the macropinosome itself is not yet available. With the aid of nanotechnology, we
have developed methodology to isolate a pure fraction of macropinosomes from PDAC cells. Having the
capability to purify macropinosomes, we are now uniquely positioned to benefit from largescale proteomics that
can provide a broad picture of this important organelle. By elucidating the molecular anatomy of KRAS-driven
macropinosomes, we will gain further insight into the regulation and function of macropinocytosis in cancer.
Moreover, having a clearer picture of the macropinosome will make us better positioned to exploit this pathway
therapeutically and deliver breakthroughs to patients.
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专著(0)
科研奖励(0)
会议论文
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批准号:10563637
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项目类别:
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资助金额:$64.74万
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财政年份:2023
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负责人:Cosimo Commisso
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依托单位:
Regulation and Function of Stromal Macropinocytosis in Pancreatic Ductal Adenocarcinoma
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批准号:10475282
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资助金额:$57.41万
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财政年份:2021
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依托单位:
Regulation and Function of Stromal Macropinocytosis in Pancreatic Ductal Adenocarcinoma
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批准号:10293358
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项目类别:
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资助金额:$58.09万
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财政年份:2021
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负责人:Cosimo Commisso
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依托单位:
Regulation of Nutrient Stress-Induced Macropinocytosis in Pancreatic Ductal Adenocarcinoma
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批准号:10475251
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项目类别:
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资助金额:$45.68万
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财政年份:2016
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负责人:Cosimo Commisso
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依托单位:
Regulation of Nutrient Stress-Induced Macropinocytosis in Pancreatic Ductal Adenocarcinoma
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批准号:10283951
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项目类别:
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资助金额:$46.61万
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财政年份:2016
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负责人:Cosimo Commisso
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依托单位:
Regulation of Nutrient Stress-Induced Macropinocytosis in Pancreatic Ductal Adenocarcinoma
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批准号:9280912
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项目类别:
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资助金额:$44.61万
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财政年份:2016
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负责人:Cosimo Commisso
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依托单位:
Regulation of Nutrient Stress-Induced Macropinocytosis in Pancreatic Ductal Adenocarcinoma
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批准号:10677661
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项目类别:
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资助金额:$45.68万
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财政年份:2016
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负责人:Cosimo Commisso
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依托单位:
Cancer Metabolism
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批准号:10174822
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项目类别:
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资助金额:$19.12万
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财政年份:1997
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负责人:Cosimo Commisso
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依托单位:
海外基金