EMT drives targetable metabolic dependencies in breast cancer
EMT 驱动乳腺癌的靶向代谢依赖性
基本信息
- 批准号:10065384
- 负责人:
- 金额:$ 3.77万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-08-03 至 2022-07-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAddressAutomobile DrivingAutophagocytosisBasement membraneBreast Cancer CellBreast Epithelial CellsCancer PrognosisCell DeathCell LineCell SurvivalCellsCholesterolCholesterol HomeostasisClinicalCuesDataDependenceDiffuseDisseminated Malignant NeoplasmDistantEndocytic VesicleEpithelialEpitheliumEstrogen receptor positiveEvaluationExtracellular MatrixExtracellular Matrix DegradationFRAP1 geneGene ExpressionGenesGrantIn VitroIndolentInvadedLDL Cholesterol LipoproteinsLaboratoriesLeadLiteratureLow Density Lipoprotein ReceptorLow-Density LipoproteinsLysosomesMalignant NeoplasmsManuscriptsMechanicsMediatingMentorsMesenchymalMetabolicMetabolismMetastatic breast cancerMicroRNAsMolecularNeoplasm MetastasisNewly DiagnosedPathway AnalysisPatientsPhasePhenotypePhysiologyPreparationProcessRegulationResearchResearch Project GrantsResistanceResourcesRoleSamplingSiteSmall Interfering RNASourceStromal CellsSupporting CellSupraoptic Vertical OphthalmoplegiaTechnical ExpertiseTechnologyTestingTherapeuticTissuesTrainingTransitional Cell NeoplasmVLDL receptorVery low density lipoproteinWorkbasebreast cancer diagnosisbreast cancer progressioncancer cellcancer subtypescell growthcell motilityepithelial to mesenchymal transitionexperienceexperimental studyextracellularin vivo Modelinsightinterestknock-downmalignant breast neoplasmmechanotransductionmetabolomicsmigrationmolecular targeted therapiesnew therapeutic targetnoveloutcome forecastparticleprotein metabolismresponserestorationsmall molecule inhibitorstandard caretargeted treatmenttherapeutic developmenttherapeutic targettooltriple-negative invasive breast carcinomatumortumor metabolismtumor microenvironmenttumor progressionuptake
项目摘要
Project Summary
Triple Negative Breast Cancer (TNBC) is an aggressive subtype representing 15-20% of newly
diagnosed breast cancer cases. Due to a lack of known molecular targets, treatment options for TNBC are
limited, and 30-50% of patients acquire resistance to standard care. I aim to better understand the metabolic
dependencies of TNBC cells to reveal novel targets that could be exploited therapeutically. TNBC cells tend to
exist in a mesenchymal-like state, having undergone epithelial-to-mesenchymal transition (EMT) during which
cells acquire a more motile and invasive phenotype. Because EMT is associated with poor breast cancer
prognosis, understanding the molecular drivers and adaptations during this process will identify targetable
dependencies of metastatic cancer cells. microRNA-200c (miR-200c) is well-established as a suppressor of
EMT that tends to be lost in TNBC. Using miR-200c as a tool to push TNBC cells into a more epithelial-like
phenotype, I have identified novel changes to cholesterol metabolism occurring during EMT. This project
delineates how EMT regulates cholesterol metabolism and the functional consequences of these changes.
In the F99 portion of this grant, I establish how reversal of EMT by miR-200c alters cholesterol
metabolism proteins including the low-density-lipoprotein (LDL) receptor (LDLR) and Niemann-Pick-Type-C1
(NPC1). LDLR is responsible for endocytosing LDL particles, which are the primary source of cholesterol for
breast tumor cells. After fusion of endocytic vesicles with the lysosome, NPC1 is specifically required for the
processing and transport of cholesterol from lysosomes to other cellular components. These changes suggest
an altered demand for cholesterol mesenchymal-like versus epithelial-like TNBC, the consequences of which
are evaluated in Aim 1B of this project. My preliminary data also demonstrates that NPC1 activity is critical to
survival of TNBC cells in vitro. In Aim 1B, I outline experiments to understand overall cholesterol uptake and
intracellular cholesterol levels during EMT and delineate the critical role of NPC1 on TNBC cell viability. This
work is the first to establish altered dependency and expression of LDLR and NPC1 in EMT and breast cancer
progression.
In the K00 phase of the proposed project, I will expand on my interest in the metabolic requirements of
the metastatic cascade. I will move into investigating how extracellular mechanical cues driven by the
extracellular matrix (ECM) drive metabolic adaptations to promote invasion and migration during metastasis.
Further, I will evaluate whether the EMT phenotype of cells influences these adaptations. Gaining a better
understanding of how cancer cell metabolism supports changing ECM and how mechanical demands
encountered during metastasis will provide insights into development of therapeutic targets within tumor
metabolism.
项目摘要
三阴性乳腺癌(TNBC)是一种侵袭性亚型,占新发乳腺癌的15-20%。
确诊乳腺癌病例。由于缺乏已知的分子靶点,TNBC的治疗选择是
有限,30-50%的患者对标准护理产生抵抗。我的目标是更好地了解新陈代谢
TNBC细胞的依赖性,以揭示可以在治疗上利用的新靶点。TNBC细胞倾向于
以间充质样状态存在,经历了上皮-间充质转化(EMT),在此期间,
细胞获得更有运动性和侵袭性的表型。因为EMT与乳腺癌的不良关系
预后,了解分子驱动因素和适应在这一过程中将确定有针对性的
转移性癌细胞的依赖性。microRNA-200 c(miR-200 c)是一种公认的抑制因子,
EMT往往会在TNBC中丢失。使用miR-200 c作为工具将TNBC细胞推向更上皮样细胞
表型,我已经确定了新的变化,胆固醇代谢发生在EMT。这个项目
描述了EMT如何调节胆固醇代谢和这些变化的功能后果。
在F99部分,我确定了miR-200 c逆转EMT如何改变胆固醇
包括低密度脂蛋白(LDL)受体(LDLR)和尼曼-匹克-C1型在内的代谢蛋白
(NPC1)。LDLR负责内吞LDL颗粒,LDL颗粒是胆固醇的主要来源,
乳腺肿瘤细胞内吞囊泡与溶酶体融合后,NPC 1是细胞内分泌所必需的。
胆固醇从溶酶体到其他细胞成分的加工和运输。这些变化表明,
对胆固醇间质样与上皮样TNBC的需求改变,其后果是
在本项目的目标1B中进行了评估。我的初步数据还表明,NPC 1的活动对
TNBC细胞在体外的存活。在目标1B中,我概述了了解总体胆固醇摄取的实验,
在EMT过程中的细胞内胆固醇水平,并描绘了NPC 1对TNBC细胞活力的关键作用。这
这项工作首次确定了LDLR和NPC 1在EMT和乳腺癌中的依赖性和表达改变
进展
在拟议项目的K 00阶段,我将扩大我对代谢要求的兴趣,
转移级联反应我将着手研究细胞外的机械信号是如何被
细胞外基质(ECM)驱动代谢适应以促进转移期间的侵袭和迁移。
此外,我将评估细胞的EMT表型是否影响这些适应。加深
了解癌细胞代谢如何支持改变ECM以及机械需求如何
在转移过程中遇到的问题将为肿瘤内治疗靶点的发展提供见解
新陈代谢.
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)
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Kathleen O'Neill其他文献
Kathleen O'Neill的其他文献
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{{ truncateString('Kathleen O'Neill', 18)}}的其他基金
EMT drives targetable metabolic dependencies in breast cancer
EMT 驱动乳腺癌的靶向代谢依赖性
- 批准号:
10228092 - 财政年份:2020
- 资助金额:
$ 3.77万 - 项目类别:
Lysosomal metabolism as a targetable driver of pancreatic cancer
溶酶体代谢作为胰腺癌的目标驱动因素
- 批准号:
10665262 - 财政年份:2020
- 资助金额:
$ 3.77万 - 项目类别:
Lysosomal metabolism as a targetable driver of pancreatic cancer
溶酶体代谢作为胰腺癌的目标驱动因素
- 批准号:
10688248 - 财政年份:2020
- 资助金额:
$ 3.77万 - 项目类别:
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