Project1: The role of intravascular pressure and shear stress on tumor cell arrest, survival and proliferation in the microvascular niche
项目1:血管内压力和剪切应力对微血管微环境中肿瘤细胞停滞、存活和增殖的作用
基本信息
- 批准号:10688247
- 负责人:
- 金额:$ 23.77万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-17 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:ActomyosinAdhesionsAnimal ModelBatimastatBlood PlateletsBlood VesselsBlood flowBreast Cancer CellBreast cancer metastasisCD44 geneCell AdhesionCell SurvivalCellsCessation of lifeChromatinChromatin StructureCirculationClinicalCoagulation ProcessComputer ModelsCoping SkillsCytoskeletonDermisEndothelial CellsEndotheliumEngineeringEnvironmentEventExhibitsExposure toExtravasationFibrinGenerationsGenetic Complementation TestGenetic TranscriptionGeometryHematologyHumanImmuneIn VitroIndividualInterventionKnowledgeLamin Type ALesionLiverMatrix MetalloproteinasesMeasuresMechanical StressMechanicsMediatingMicroscopicModelingMolecularMorphologyNeoplasm Circulating CellsNeoplasm MetastasisNuclearOrganOrgan ModelOutcomePeripheralPhenotypePhysical environmentPopulationProbabilityProcessProliferatingPropertyProteolysisResolutionRho-associated kinaseRoleSignal PathwaySourceStressStromal CellsStudy modelsSystemTechniquesTestingTherapeuticThrombusTissuesTropismcancer cellcopingcoping mechanismdesigndruggable targetexperienceexperimental studyextracellularhemodynamicshigh resolution imaginghuman diseaseinhibitorinsightkinase inhibitorknock-downmigrationmonolayerneoplastic cellnovel therapeutic interventionnovel therapeuticsoverexpressionpermissivenesspressurepreventself assemblyshear stresssingle-cell RNA sequencingstressortranscriptomicstriple-negative invasive breast carcinoma
项目摘要
Project 1: SUMMARY
Metastatic colonization requires that circulating tumor cells (CTCs) overcome the physical stressors and homeostatic
barriers that make successful metastasis an unlikely outcome. Very little is known about metastatic subpopulations, the
adaptations that allow them to circumvent homeostatic barriers, and the mechanisms used to cope with these stressors
and either proliferate or enter into dormancy. The intravascular environment is known to be inhospitable to CTCs, yet
several lines of clinical evidence indicate that physical interactions with activated platelets, fibrin thrombi, immune cells
and the formation of clusters with other cancer cells influences metastatic potential. Furthermore, the mechanism of
extravasation within the microvasculature is mediated by endothelial interactions, cytoskeletal forces, nuclear
deformations, and matrix proteolysis. It has long been recognized that metastatic tropism is determined by intrinsic
organ properties. We hypothesize that secondary colonization is the culmination of a sequence of low probability
events for which only a small subpopulation of CTCs has adapted to cope with these stressors. To investigate the
mechanisms of arrest, extravasation, and colonization we have developed in vitro vascular networks that recapitulate
the geometry and function of the microvascular networks where circulating tumor cells initiate metastatic lesions.
Importantly, we are able to precisely engineer the microvascular environment by controlling cellular constituents,
extracellular components, and the physical stressors to systematically distinguish the effect of specific perturbations on
cancer cell arrest, transmigration, and colonization with high temporal and spatial resolution. In Aim 1, we create
cancer cell thrombi and clusters to determine the effect of interactions with platelets, fibrin, and cancer cells on the
arrest, transmigration, and colonization. In Aim 2, we extend the capabilities of our microvascular platforms to
recapitulate the organ-specific microvascular environments of liver and dermis to examine combined effects of different
flow and endothelial barrier function. In Aim 3, we will use specific molecular interventions to target tumor cell
adhesion, contractility, nuclear deformability, and matrix degradation to quantify the effect on intravascular adhesion,
transendothelial migration, and long-term extravascular fate. In Aim 4, we will measure nuclear deformation and
quantify chromatin reorganization during transmigration and determine if quantitative measures of chromatin
reorganization fates extravasated cells to a dormant phenotype (Core B). Taken together, we hypothesize that
methodical in vitro observation combined with and validated by intravital studies (Project 2) and computational
modeling (Core A) will lead to new insights regarding the specific mechanisms that enable CTCs to circumvent physical
stressors. By engineering the physical environment, we will generate the knowledge leading to novel therapeutic
opportunities to block or reverse the coping phenotype.
项目1:摘要
转移性定植需要循环肿瘤细胞(CTC)克服物理应激源并维持体内平衡。
使成功转移成为不太可能的结果的障碍。人们对转移性亚群知之甚少,
使他们能够绕过稳态障碍的适应,以及用于科普这些压力源的机制
要么增殖要么休眠已知血管内环境不适合CTC,然而,
一些临床证据表明,与活化血小板、纤维蛋白血栓、免疫细胞
并且与其它癌细胞形成簇会影响转移潜力。此外,
微血管系统内的外渗是由内皮相互作用、细胞骨架力、细胞核相互作用
变形和基质蛋白水解。长期以来,人们已经认识到,转移性是由内源性的
器官特性我们假设二次定植是一系列低概率
只有一小部分CTC适应科普这些应激源。探讨
我们已经开发出体外血管网络,概括了
微血管网络的几何形状和功能,循环肿瘤细胞在微血管网络中引发转移性病变。
重要的是,我们能够通过控制细胞成分来精确地设计微血管环境,
细胞外成分和物理应激源,以系统地区分特定扰动对
以高时间和空间分辨率检测癌细胞停滞、迁移和定殖。在目标1中,我们创建
癌细胞血栓和簇,以确定与血小板、纤维蛋白和癌细胞的相互作用对
逮捕、穿越和殖民。在目标2中,我们将微血管平台的功能扩展到
概括肝脏和真皮的器官特异性微血管环境,以检查不同药物的联合作用。
血流和内皮屏障功能。在目标3中,我们将使用特定的分子干预措施来靶向肿瘤细胞
粘附性、收缩性、核变形性和基质降解,以量化对血管内粘附的影响,
跨内皮迁移和长期血管外命运。在目标4中,我们将测量核变形,
在迁移过程中定量染色质重组,并确定染色质的定量测量
重组使外渗的细胞变成休眠表型(核心B)。综合考虑,我们假设
体外观察结合活体研究(项目2)和计算方法,并通过活体研究进行验证
模型(核心A)将导致新的见解的具体机制,使CTC规避物理
压力源通过设计物理环境,我们将产生导致新的治疗方法的知识,
阻止或逆转应对表型的机会。
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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{{ truncateString('ROGER D KAMM', 18)}}的其他基金
Mechanical determinants of organ-selective metastatic colonization, dormancy and outgrowth
器官选择性转移定植、休眠和生长的机械决定因素
- 批准号:
10490281 - 财政年份:2021
- 资助金额:
$ 23.77万 - 项目类别:
Project1: The role of intravascular pressure and shear stress on tumor cell arrest, survival and proliferation in the microvascular niche
项目1:血管内压力和剪切应力对微血管微环境中肿瘤细胞停滞、存活和增殖的作用
- 批准号:
10912091 - 财政年份:2021
- 资助金额:
$ 23.77万 - 项目类别:
Project1: The role of intravascular pressure and shear stress on tumor cell arrest, survival and proliferation in the microvascular niche
项目1:血管内压力和剪切应力对微血管微环境中肿瘤细胞停滞、存活和增殖的作用
- 批准号:
10490283 - 财政年份:2021
- 资助金额:
$ 23.77万 - 项目类别:
Admin: Mechanical determinants of organ-selective metastatic colonization, dormancy and outgrowth
管理员:器官选择性转移定植、休眠和生长的机械决定因素
- 批准号:
10688245 - 财政年份:2021
- 资助金额:
$ 23.77万 - 项目类别:
Mechanical determinants of organ-selective metastatic colonization, dormancy and outgrowth
器官选择性转移定植、休眠和生长的机械决定因素
- 批准号:
10688244 - 财政年份:2021
- 资助金额:
$ 23.77万 - 项目类别:
Studying E-cadherin dynamics during extravasation and metastatic colonization
研究外渗和转移定植过程中 E-钙粘蛋白的动态
- 批准号:
10831158 - 财政年份:2021
- 资助金额:
$ 23.77万 - 项目类别:
Admin: Mechanical determinants of organ-selective metastatic colonization, dormancy and outgrowth
管理员:器官选择性转移定植、休眠和生长的机械决定因素
- 批准号:
10490282 - 财政年份:2021
- 资助金额:
$ 23.77万 - 项目类别:
Mechanical determinants of organ-selective metastatic colonization, dormancy and outgrowth
器官选择性转移定植、休眠和生长的机械决定因素
- 批准号:
10271565 - 财政年份:2021
- 资助金额:
$ 23.77万 - 项目类别:
Admin: Mechanical determinants of organ-selective metastatic colonization, dormancy and outgrowth
管理员:器官选择性转移定植、休眠和生长的机械决定因素
- 批准号:
10271566 - 财政年份:2021
- 资助金额:
$ 23.77万 - 项目类别:
Project1: The role of intravascular pressure and shear stress on tumor cell arrest, survival and proliferation in the microvascular niche
项目1:血管内压力和剪切应力对微血管微环境中肿瘤细胞停滞、存活和增殖的作用
- 批准号:
10271567 - 财政年份:2021
- 资助金额:
$ 23.77万 - 项目类别:
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