Tumor Cell Dependence on Host Metabolism
肿瘤细胞对宿主代谢的依赖性
基本信息
- 批准号:9333585
- 负责人:
- 金额:$ 44.07万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-08-07 至 2022-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAmino AcidsAnabolismAntineoplastic AgentsArginineAutophagocytosisBiomassBlood CirculationBypassCharacteristicsConsumptionDependenceDependencyDietDietary InterventionExplosionFatty AcidsFatty acid glycerol estersFermentationGenerationsGeneticGlucoseGlutamineGlutathioneGlycineGrowthHomeostasisImpairmentImplantIn VitroIntakeIsotopesK-ras mouse modelMalignant NeoplasmsMalignant neoplasm of lungMapsMetabolicMetabolic PathwayMetabolismMethionineMethodsModelingMolecularMonitorMusNADPNon-Essential Amino AcidNormal tissue morphologyNucleotidesNutrientNutritional SupportOxidation-ReductionPathway interactionsPlasmaPlayRoleRouteSerineSourceTechniquesTestingTherapeuticTimeTissuesTracerTreatment ProtocolsVascular blood supplyWarburg EffectWorkasparaginasecancer cellcancer therapyclinical efficacycomparativedesignin vivointerestinventionmelanomametabolomicsneoplastic cellnovel strategiesresponsetumortumor growthtumor metabolismuptake
项目摘要
ABSTRACT
Rapid fermentation of glucose to lactate (the “Warburg effect”) was the first molecular characteristic assigned
to cancer. Recent years have seen an explosion of interest in the metabolic capabilities of tumor cells,
including up-regulated anabolism, redox defense, and alternative routes of nutrient acquisition such as
macropinocytosis and autophagy. While these cellular capabilities play a critical role, metabolically, tumors
ultimately depend on circulating nutrients provided by the host. The extent to which tumors generate
energy and biomass building blocks from a few preferred circulating nutrients like glucose, versus uptake
diverse nutrients to minimize their own biosynthetic work, remains, however, poorly understood. For example,
many tumors upregulate serine biosynthesis. At the same time, tumor growth is sensitive to dietary serine
intake. Which contributes more—circulating serine from the diet or serine synthesized in the tumor?
While substantial efforts have been made to understand the essential metabolic pathways within tumor cells,
comparatively little effort has gone into understanding the tumor's dependency on host metabolism. We have
surprisingly observed that consumption of circulating nutrients by tumors is profoundly different from
that of cultured cancer cells. We have also surprisingly observed that host autophagy is important for
sustaining circulating nutrients and for the growth of implanted tumors (where autophagy remains
intact). These findings highlight the potential for host metabolic processes to impact tumor growth. What are
the critical circulating nutrients for tumors? How is host metabolism altered by autophagy deficiency? Which
are the critical changes that impair tumor growth? More broadly, how can tumor dependency on host
metabolism be exploited therapeutically? To address these questions, we will employ state-of-the-art isotope
tracer techniques to murine tumor models of lung cancer and melanoma. Specifically, we will address the role
of host metabolism in mouse models of K-Ras lung cancer, and B-Raf lung cancer and melanoma:
Aim 1: Identify the contributions of circulating nutrients and internal tumor metabolic pathways to lung
cancer and melanoma growth. We hypothesize that, rather than using glucose and glutamine as their
primary substrates, tumors in vivo consume a broad diversity of circulating nutrients, including amino acids,
fats, and lactate, thereby minimizing biosynthetic requirements and enhancing metabolic robustness.
Aim 2: Determine the mechanism underlying dependence of tumors on host autophagy. We hypothesize
that host autophagy is required to maintain circulating nutrients to support tumor growth.
Aim 3: Assess the therapeutic potential of modulating circulating metabolites. We hypothesize that
decreasing circulating levels of nutrients including arginine, methionine, and glycine will have anti-tumor
activity.
摘要
葡萄糖快速发酵成乳酸(“瓦尔堡效应”)是第一个被指定的分子特征
到癌症近年来,人们对肿瘤细胞的代谢能力产生了极大的兴趣,
包括上调的抗氧化剂、氧化还原防御和营养获取的替代途径,
巨胞饮和自噬。虽然这些细胞能力在代谢方面发挥着关键作用,但肿瘤
最终取决于宿主提供的循环营养。肿瘤产生的程度
能量和生物量的构建块从一些优选的循环营养素,如葡萄糖,与摄取
然而,人们对各种营养素如何最大限度地减少其自身的生物合成工作仍然知之甚少。比如说,
许多肿瘤上调丝氨酸生物合成。同时,肿瘤生长对膳食丝氨酸敏感
摄入哪一个从饮食中贡献了更多循环的丝氨酸,还是在肿瘤中合成的丝氨酸?
虽然已经做出了大量的努力来了解肿瘤细胞内的基本代谢途径,
相对而言,很少有人致力于了解肿瘤对宿主代谢的依赖性。我们有
令人惊讶地观察到,肿瘤对循环营养物的消耗与
即培养的癌细胞。我们还惊奇地观察到,宿主自噬对于
维持循环营养和用于植入肿瘤的生长(其中自噬仍然存在
完整)。这些发现强调了宿主代谢过程影响肿瘤生长的潜力。是什么
肿瘤的关键循环营养物质自噬缺陷如何改变宿主的代谢?这
是阻碍肿瘤生长的关键变化吗更广泛地说,肿瘤如何依赖于宿主
新陈代谢可以用于治疗吗为了解决这些问题,我们将使用最先进的同位素
示踪技术用于肺癌和黑色素瘤的鼠肿瘤模型。具体而言,我们将讨论
K-Ras肺癌、B-Raf肺癌和黑色素瘤小鼠模型中的宿主代谢:
目的1:确定循环营养物质和肿瘤内部代谢途径对肺的贡献
癌症和黑色素瘤生长。我们假设,与其使用葡萄糖和谷氨酰胺作为它们的
作为主要底物,体内肿瘤消耗多种多样的循环营养物,包括氨基酸,
脂肪和乳酸盐,从而使生物合成需求最小化并增强代谢稳健性。
目的2:探讨肿瘤对宿主自噬依赖性的机制。我们假设
宿主自噬是维持循环营养以支持肿瘤生长所必需的。
目的3:评估调节循环代谢物的治疗潜力。我们假设
降低包括精氨酸、甲硫氨酸和甘氨酸在内的营养物质的循环水平将具有抗肿瘤作用。
活动
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 }}
JOSHUA D RABINOWITZ其他文献
JOSHUA D RABINOWITZ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('JOSHUA D RABINOWITZ', 18)}}的其他基金
Metabolism in Action: Quantitative Fluxes in Mammals
新陈代谢在行动:哺乳动物的数量通量
- 批准号:
9535989 - 财政年份:2016
- 资助金额:
$ 44.07万 - 项目类别:
Mechanisms and consequences of metabolic manipulation by human cytomegalovirus
人类巨细胞病毒代谢操纵的机制和后果
- 批准号:
8532816 - 财政年份:2012
- 资助金额:
$ 44.07万 - 项目类别:
Mechanisms and consequences of metabolic manipulation by human cytomegalovirus
人类巨细胞病毒代谢操纵的机制和后果
- 批准号:
8697006 - 财政年份:2012
- 资助金额:
$ 44.07万 - 项目类别:
Mechanisms and consequences of metabolic manipulation by human cytomegalovirus
人类巨细胞病毒代谢操纵的机制和后果
- 批准号:
8343995 - 财政年份:2012
- 资助金额:
$ 44.07万 - 项目类别:
Identification of Metabolic Vulnerabilities of Ras-Driven Cancer Cells
Ras 驱动的癌细胞代谢脆弱性的鉴定
- 批准号:
8686780 - 财政年份:2012
- 资助金额:
$ 44.07万 - 项目类别:
Identification of Metabolic Vulnerabilities of Ras-Driven Cancer Cells
Ras 驱动的癌细胞代谢脆弱性的鉴定
- 批准号:
8370625 - 财政年份:2012
- 资助金额:
$ 44.07万 - 项目类别:
Identification of Metabolic Vulnerabilities of Ras-Driven Cancer Cells
Ras 驱动的癌细胞代谢脆弱性的鉴定
- 批准号:
8525354 - 财政年份:2012
- 资助金额:
$ 44.07万 - 项目类别:
Mass Spectrometry Methods for Probing Metabolic Dynamics in Normal & Cancer Cells
探测正常代谢动态的质谱方法
- 批准号:
7432649 - 财政年份:2008
- 资助金额:
$ 44.07万 - 项目类别:
Mass Spectrometry Methods for Probing Metabolic Dynamics in Normal & Cancer Cells
探测正常代谢动态的质谱方法
- 批准号:
7615679 - 财政年份:2008
- 资助金额:
$ 44.07万 - 项目类别:
相似海外基金
Double Incorporation of Non-Canonical Amino Acids in an Animal and its Application for Precise and Independent Optical Control of Two Target Genes
动物体内非规范氨基酸的双重掺入及其在两个靶基因精确独立光学控制中的应用
- 批准号:
BB/Y006380/1 - 财政年份:2024
- 资助金额:
$ 44.07万 - 项目类别:
Research Grant
Quantifying L-amino acids in Ryugu to constrain the source of L-amino acids in life on Earth
量化 Ryugu 中的 L-氨基酸以限制地球生命中 L-氨基酸的来源
- 批准号:
24K17112 - 财政年份:2024
- 资助金额:
$ 44.07万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Collaborative Research: RUI: Elucidating Design Rules for non-NRPS Incorporation of Amino Acids on Polyketide Scaffolds
合作研究:RUI:阐明聚酮化合物支架上非 NRPS 氨基酸掺入的设计规则
- 批准号:
2300890 - 财政年份:2023
- 资助金额:
$ 44.07万 - 项目类别:
Continuing Grant
Basic research toward therapeutic strategies for stress-induced chronic pain with non-natural amino acids
非天然氨基酸治疗应激性慢性疼痛策略的基础研究
- 批准号:
23K06918 - 财政年份:2023
- 资助金额:
$ 44.07万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Molecular mechanisms how arrestins that modulate localization of glucose transporters are phosphorylated in response to amino acids
调节葡萄糖转运蛋白定位的抑制蛋白如何响应氨基酸而被磷酸化的分子机制
- 批准号:
23K05758 - 财政年份:2023
- 资助金额:
$ 44.07万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Molecular recognition and enantioselective reaction of amino acids
氨基酸的分子识别和对映选择性反应
- 批准号:
23K04668 - 财政年份:2023
- 资助金额:
$ 44.07万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Design and Synthesis of Fluorescent Amino Acids: Novel Tools for Biological Imaging
荧光氨基酸的设计与合成:生物成像的新工具
- 批准号:
2888395 - 财政年份:2023
- 资助金额:
$ 44.07万 - 项目类别:
Studentship
Structurally engineered N-acyl amino acids for the treatment of NASH
用于治疗 NASH 的结构工程 N-酰基氨基酸
- 批准号:
10761044 - 财政年份:2023
- 资助金额:
$ 44.07万 - 项目类别:
Lifestyle, branched-chain amino acids, and cardiovascular risk factors: a randomized trial
生活方式、支链氨基酸和心血管危险因素:一项随机试验
- 批准号:
10728925 - 财政年份:2023
- 资助金额:
$ 44.07万 - 项目类别:
Single-molecule protein sequencing by barcoding of N-terminal amino acids
通过 N 端氨基酸条形码进行单分子蛋白质测序
- 批准号:
10757309 - 财政年份:2023
- 资助金额:
$ 44.07万 - 项目类别: