Protrusion plasticity during in vivo tumor cell migration
体内肿瘤细胞迁移过程中的突出可塑性
基本信息
- 批准号:9321473
- 负责人:
- 金额:$ 19.22万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-08-01 至 2019-07-31
- 项目状态:已结题
- 来源:
- 关键词:ActinsAddressAdvisory CommitteesAffectAnatomyAnimal ModelAreaBehaviorBiologyBiophotonicsBiosensorBlood VesselsBreast Cancer CellBreast Cancer ModelBreast cancer metastasisCell CommunicationCell PolarityCellsCellular MorphologyCellular biologyChemotaxisCollaborationsCollagen FiberComplexCuesCustomCytoskeletonDataDevelopmentDiagnosisDimensionsDiseaseEarly treatmentEnvironmentEventExtracellular MatrixFacultyFluorescence Resonance Energy TransferGoalsGuanosine Triphosphate PhosphohydrolasesHomeostasisImageImaging TechniquesIn VitroInstitutionKnowledgeLaboratoriesLeadLinkMacrophage Colony-Stimulating Factor ReceptorMalignant NeoplasmsMediatingMembraneMentorsMicroscopeMicroscopyModalityMoldsMolecularMonitorMovementNeoplasm MetastasisOutcomeOutputPathway interactionsPatternPeer ReviewPhenotypePhysiologicalPlayPostdoctoral FellowPrimary NeoplasmProcessProtein FamilyProteinsPseudopodiaPublicationsReceptor SignalingRecruitment ActivityRegulationResearchResolutionResourcesRoleShapesSignal PathwaySignal TransductionSignaling ProteinSpainStromal CellsSystemTechniquesTertiary Protein StructureTrainingTranslatingTumor Cell InvasionTumor Cell MigrationUniversitiesWorkXenograft Modelbeta Actincancer cellcareer developmentcell behaviorcell motilitydesigndrug developmentexperimental studyextracellularhuman diseaseimaging systemimprovedin vitro Modelin vivoin vivo imaginginnovationinstructorinterestintravital imagingmacrophagemembermigrationmultidisciplinarymultiphoton imagingneoplastic cellnovelpost-doctoral trainingpublic health relevancespatiotemporaltargeted treatmenttumortumor microenvironmenttumor progression
项目摘要
DESCRIPTION (provided by applicant): Dr. Bravo-Cordero obtained his degree in biology at Autonoma University of Madrid, Spain. After completing his doctorate work, in which he used high-resolution confocal imaging techniques to study cancer cell biology, he continued his training in the area of state-of-the-art imaging in the laboratories of Dr. John Condeelis and Dr. Louis Hodgson. During postdoctoral training, Dr. Bravo-Cordero focused on understanding how RhoGTPases are spatiotemporally regulated during breast cancer cell migration and invasion. He w a s trained in techniques such as FRET microscopy as well as FRET biosensors imaging to address these questions. His work to date has resulted in 23 peer-review publications. Recent work has shown that metastasis of tumor cells is affected by the extracellular microenvironment in which the cells are located. In order to understand the mechanisms of tumor cell metastasis and the activation of the intracellular signals, high-resolution microscopy techniques like multiphoton imaging is an ideal modality to observe tumor cells inside their physiological environment. In vitro models are limited in their complexity, thus using animal models that recapitulate the disease, will be a more effective way to address questions that could not be addressed with in vitro systems. Dr. Bravo Cordero has been trained in techniques such as multiphoton in vivo imaging and FRET microscopy in order to understand cell signaling in vivo. This training makes it possible to lead a laboratory that integrates animal models, multiphoton imaging and FRET- biosensor imaging in vivo to understand mechanisms of tumor cell metastasis. Environment: Advisory committee of the PI included Dr. John Condeelis, Co-Chair of Anatomy Department and Biophotonic Center at Einstein. His lab and the Center create a multidisciplinary environment focused on answering mechanisms of human diseases, such as cancer, through use of microscopy. The Center is well known for its shared imaging resources and Innovation Laboratory, in which new microscopes are custom-built to accommodate specific needs of different projects. Other members of the advisory committee are: Dr. Louis Hodgson, he is an expert in FRET biosensor imaging and FRET biosensor design and Dr. Richard Stanley, he is an expert on macrophages biology and CSF-1 receptor signaling, he also studies F-Bar domain proteins in the context of chemotaxis. Dr. Richard Stanley is also a renowned mentor. Einstein is an institution that values collaboration and insists on career development of postdoctoral fellows, instructors and junior faculty. Research: Motility and invasion are crucial steps for multiple processes from development and homeostasis to metastasis. In order for cells to move, they must form membrane extensions to propel themselves through the extracellular matrix. Thus, understanding the molecular pathways that drive spatiotemporal control of protrusion formation is a fundamental question to be answered. The tumor microenvironment is composed of collagen fibers, stromal cells and blood vessels that, in combination, will influence the motility behavior of tumor cells. RhoGTPases are master regulators of cytoskeleton dynamics being tightly regulated by multiple proteins. A family of proteins containing Bar-domains acts at the interface between membrane plasticity and RhoGTPases signaling, and these proteins have emerged as important regulators of GTPases and membrane shape. The final migratory output of a tumor cell will be dictated by the extracellular matrix conditions and that will be translated through a complex signaling system that include BAR proteins and RhoGTPases to induce cytoskeleton rearrangements. Signaling pathways through RhoGTPases have been widely studied in vitro, but the mechanism that regulates GTPase activation in vivo is still unknown. To address the link between tumor microenvironment, motility behavior and RhoGTPases signaling is necessary to combine multiphoton intravital imaging with FRET-biosensors imaging. Two different types of protrusion have been shown to mediate tumor invasion, lamellipodia and invadopodia. To date, it is not clear the contribution of each of them to motility in vivo and tumor intravasation. My preliminary results have shown that tumor cells expressing β-actin-TagRFP-T as a marker for pseudopodia protrusions show that cell extending membrane protrusion in order to move have enriched in action. Aim 1 will explore how signaling mediated by the GTPases RhoA and RhoC determine the formation of invadopodia and pseudopodia protrusions depending on the extracellular matrix context. By using FRET biosensors in vivo, the activation pattern of these GTPases will be analyzed in these different protrusions. In preliminary experiments the Bar protein srGAP1, which regulates RhoGTPases, is recruited to pseudopodia and invadopodia protrusions of tumor cells. Aim 2 will explore the role of srGAP1 in establishing lamellipodia and invadopodia protrusions through RhoGTPases regulation. Aim 3 will explore the role of srGAP1 in tumor cell dissemination and metastasis in vivo. Results of this study will lead to a better understanding of the interplay among microenvironment components, GTPase signaling and cytoskeleton rearrangements during tumor progression and the results will be used to improve diagnosis and treatment of early metastasis.
描述(由申请人提供):Bravo-Cordero 博士在西班牙马德里自治大学获得生物学学位。在完成他的博士工作后,他使用高分辨率共聚焦成像技术研究癌细胞生物学。在博士后培训期间,Bravo-Cordero 博士在 John Condeelis 博士和 Louis Hodgson 博士的实验室接受最先进成像领域的培训。 RhoGTPases 在乳腺癌细胞迁移和侵袭过程中受到时空调节。他接受了 FRET 显微镜和 FRET 生物传感器成像等技术的培训,迄今为止,他的工作已发表了 23 篇同行评审出版物。肿瘤细胞的转移受到细胞所处的细胞外微环境的影响,为了了解肿瘤细胞转移的机制和细胞内信号的激活,多光子成像等高分辨率显微镜技术是观察生理环境内肿瘤细胞的理想方式,但体外模型的复杂性有限,因此使用重现疾病的动物模型将是解决可能存在的问题的更有效方法。 Bravo Cordero 博士接受过多光子体内成像和 FRET 显微镜等技术的培训,以便了解体内细胞信号传导。这种培训使领导一个整合动物的实验室成为可能。模型、多光子成像和体内 FRET 生物传感器成像,以了解肿瘤细胞转移的机制。 环境:PI 顾问委员会包括爱因斯坦解剖学系和生物光子中心联合主席 John Condeelis 博士。该中心以其共享的成像资源和创新实验室而闻名,其中新的显微镜是定制的。以满足不同项目的具体需求。顾问委员会的其他成员包括:Louis Hodgson 博士,他是 FRET 生物传感器成像和 FRET 生物传感器设计方面的专家;Richard Stanley 博士,他是巨噬细胞生物学和 CSF-1 方面的专家。受体信号传导,他还研究趋化性背景下的F-Bar结构域蛋白。理查德·爱因斯坦博士也是一位重视合作并坚持博士后、导师职业发展的机构。研究:运动和侵袭是从发育、稳态到转移的多个过程的关键步骤。为了使细胞移动,它们必须形成膜延伸以推动自身穿过细胞外基质。因此,了解驱动的分子途径。突起形成的时空控制是一个需要回答的基本问题。肿瘤微环境由胶原纤维、基质细胞和血管组成,它们共同影响肿瘤细胞的运动行为。是细胞骨架动力学的主要调节因子,受到多种蛋白质的严格调节,含有 Bar 结构域的蛋白质家族作用于膜可塑性和 RhoGTP 酶信号传导之间的界面,并且这些蛋白质已成为 GTP 酶和膜最终迁移输出的重要调节因子。肿瘤细胞的信号通路将由细胞外基质条件决定,并通过包括 BAR 蛋白和 RhoGTP 酶在内的复杂信号系统进行翻译,以诱导细胞骨架信号重排。通过 RhoGTPase 的途径已在体外得到广泛研究,但调节体内 GTPase 激活的机制仍不清楚。为了解决肿瘤微环境、运动行为和 RhoGTPase 信号传导之间的联系,有必要将多光子活体成像与 FRET 生物传感器成像结合起来。不同类型的突起已被证明可介导肿瘤侵袭、片状伪足和侵袭伪足,迄今为止,尚不清楚它们各自对肿瘤侵袭的贡献。我的初步结果表明,表达 β-actin-TagRFP-T 作为伪足突起标记的肿瘤细胞表明,为了移动而延伸的细胞膜突起已丰富地发挥作用。通过使用 FRET 生物传感器,GTP 酶 RhoA 和 RhoC 介导的细胞外基质决定了侵袭伪足和伪足突出的形成。在体内,将分析这些 GTP 酶在这些不同突起中的激活模式。在初步实验中,调节 RhoGTP 酶的 Bar 蛋白 srGAP1 被招募到肿瘤细胞的伪足和侵袭伪足突起中,目的 2 将探讨 srGAP1 在建立板状伪足中的作用。 Aim 3 将探讨通过 RhoGTPases 调节的侵袭伪足突起的作用。这项研究的结果将有助于更好地了解肿瘤进展过程中微环境成分、GTPase 信号传导和细胞骨架重排之间的相互作用,并将其结果用于改善早期转移的诊断和治疗。
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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Jose Javier Bravo-Cordero其他文献
Jose Javier Bravo-Cordero的其他文献
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{{ truncateString('Jose Javier Bravo-Cordero', 18)}}的其他基金
IMAT-ITCR Collaboration: Artificial intelligence enhanced breast cancer dormancy cell classification-based organelle-morphology and topology
IMAT-ITCR 合作:人工智能增强乳腺癌休眠细胞分类的细胞器形态和拓扑
- 批准号:
10884760 - 财政年份:2023
- 资助金额:
$ 19.22万 - 项目类别:
Intersectional genetics-based biosensors for dormant cancer cells
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- 批准号:
10612300 - 财政年份:2023
- 资助金额:
$ 19.22万 - 项目类别:
Recording the natural history of cancer progression using a Crainbow model of HER2+ cancer
使用 HER2 癌症的 Crainbow 模型记录癌症进展的自然史
- 批准号:
10437462 - 财政年份:2022
- 资助金额:
$ 19.22万 - 项目类别:
Recording the natural history of cancer progression using a Crainbow model of HER2+ cancer
使用 HER2 癌症的 Crainbow 模型记录癌症进展的自然史
- 批准号:
10630320 - 财政年份:2022
- 资助金额:
$ 19.22万 - 项目类别:
Defining the role of type III collagen and the collagen-binding receptor DDR1 in metastatic dormancy
定义 III 型胶原和胶原结合受体 DDR1 在转移休眠中的作用
- 批准号:
10263927 - 财政年份:2020
- 资助金额:
$ 19.22万 - 项目类别:
Defining the role of type III collagen and the collagen-binding receptor DDR1 in metastatic dormancy
定义 III 型胶原和胶原结合受体 DDR1 在转移休眠中的作用
- 批准号:
10653992 - 财政年份:2020
- 资助金额:
$ 19.22万 - 项目类别:
Defining the role of type III collagen and the collagen-binding receptor DDR1 in metastatic dormancy
定义 III 型胶原和胶原结合受体 DDR1 在转移休眠中的作用
- 批准号:
10439836 - 财政年份:2020
- 资助金额:
$ 19.22万 - 项目类别:
Protrusion plasticity during in vivo tumor cell migration
体内肿瘤细胞迁移过程中的突出可塑性
- 批准号:
9534544 - 财政年份:2016
- 资助金额:
$ 19.22万 - 项目类别:
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