Impact of Cytoskeletal Regulators on Cancer Cell Stromal Invasion
细胞骨架调节剂对癌细胞基质侵袭的影响
基本信息
- 批准号:10291629
- 负责人:
- 金额:$ 5.94万
- 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:2020-11-16 至 2022-06-30
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalActinsAffectAmerican Association of Cancer ResearchBehaviorBlood CirculationBlood VesselsBreast Cancer CellBreast Cancer cell lineCancer ModelCell LineCell membraneCell-Matrix JunctionCellsCellular StructuresCollagenComplexCytoskeletonDisease ResistanceDistantDropsDrosophila genusEducationExtracellular MatrixExtravasationGenesGoalsHairHomologous GeneHumanImmune systemImmunologistImmunologyImmunotherapyInstitutesIntegrin beta4Intermediate FilamentsInvadedKeratinKnowledgeLATS1 geneLaboratoriesLearningMalignant - descriptorMalignant NeoplasmsMammary NeoplasmsManuscriptsMethodsMicrofluidic MicrochipsMicrofluidicsMicrotubulesModelingMonitorNeoplasm MetastasisOncogenesOrganPathway interactionsPhenotypePhosphotransferasesPhysiologicalPositioning AttributeProteinsPublishingRNA interference screenRegulationReportingResearchResearch PersonnelResearch ProposalsRoleScientistSeriesShapesSignal PathwaySignal TransductionStromal InvasionStromal NeoplasmStructureTherapeuticTissuesTrainingTranscription CoactivatorTumor Suppressor ProteinsUp-RegulationVimentinWorkZebrafishcancer cellcancer invasivenesscell motilitycrosslinkexperiencein vitro Modelinnovationinsightinterestmatrigelmeetingsnovelrecruitrhotriple-negative invasive breast carcinomatumortumor immunology
项目摘要
Cancer cell invasion of stromal tissues requires a complex interplay between major components of the
cytoskeleton. This interplay is governed by cytoskeletal regulators, which endow cancer cells with the ability to
dynamically alter their structure in order to invade through stromal tissue when metastasizing. To determine
critical modulators of invasion, I was part of a collaborative team that employed RNAi screening to identify
pathways required for cancer cell attachment to, and invasion though, endothelia. Two cytoskeletal regulators
emerged as top hits from the screen: keratin-associated protein 5-5 (Krtap5-5) and the MST3 kinase. The first
part of my dissertation (Aim 1) involved characterizing Krtap5-5, a regulator of keratin intermediate filaments
that had no previous reported role in cancer, yet I have determined that it is rate-limiting for the vascular
invasive phenotype of cancer cells. The remainder of my dissertation (Aim 2) is now focused on MST3, an
actin cytoskeleton regulator that is one of the five known mammalian MST homologues of the Drosophila
Hippo kinase. This research proposal will first explore whether the MST3 kinase is required for stromal
invasion by triple-negative breast cancer cell lines, with the hypothesis that MST3 may represent a unique
cytoskeletal vulnerability for this often aggressive and therapeutically resistant disease. MST3's role in stromal
invasion will be assessed in a series of models often used to predict metastatic spread, one of which is a
cutting-edge microfluidic device. Potential crosstalk between MST3 and the Hippo signaling pathway will also
be studied by focusing on important signaling nodes of the actin cytoskeleton, namely Rho and Rac. Upon
completion, my dissertation will produce distinct insights into the impact of cytoskeletal regulators on cancer
cell invasion of the stroma. After graduating, I seek to expand my research experience in tumor-stromal
crosstalk to include cells of the immune system (Aim 3) and plan to continue my education as a postdoctoral
researcher.
癌细胞侵入间质组织需要癌细胞主要成分之间复杂的相互作用。
细胞骨架这种相互作用由细胞骨架调节剂控制,细胞骨架调节剂赋予癌细胞以下能力:
动态地改变它们的结构,以便在转移时通过基质组织侵入。以确定
作为入侵的关键调节剂,我是一个合作团队的一员,该团队采用RNAi筛选来识别
癌细胞附着和侵入内皮所需的途径。两种细胞骨架调节因子
出现在筛选的最高命中:角蛋白相关蛋白5-5(Krtap 5 -5)和MST 3激酶。第一
我的论文(目标1)中有一部分涉及到对Krtap 5 -5的特性分析,它是一种角蛋白中间丝的调节剂
以前没有报道过它在癌症中的作用,但我已经确定它是血管紧张素转换酶的限速酶。
癌细胞的侵袭表型。我论文的其余部分(目标2)现在集中在MST 3上,
肌动蛋白细胞骨架调节因子,是已知的果蝇的五种哺乳动物MST同源物之一
河马激酶。这项研究计划将首先探讨MST 3激酶是否是基质细胞所必需的。
三阴性乳腺癌细胞系的侵袭,假设MST 3可能代表了一种独特的
细胞骨架的脆弱性,这种往往侵略性和治疗耐药的疾病。MST 3在基质中的作用
将在一系列常用于预测转移扩散的模型中评估侵袭,其中之一是
尖端的微流体装置MST 3和Hippo信号通路之间的潜在串扰也将
通过关注肌动蛋白细胞骨架的重要信号节点,即Rho和Rac来研究。后
完成后,我的论文将产生独特的见解,细胞骨架调节剂对癌症的影响
间质的细胞侵入。毕业后,我寻求扩大我的研究经验,在肿瘤间质
我的计划是将免疫系统的细胞包括在内(目标3),并计划继续我的博士后教育
研究员
项目成果
期刊论文数量(0)
专著数量(0)
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Eric Berens的其他文献
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{{ truncateString('Eric Berens', 18)}}的其他基金
Impact of Cytoskeletal Regulators on Cancer Cell Stromal Invasion
细胞骨架调节剂对癌细胞基质侵袭的影响
- 批准号:
10303071 - 财政年份:2020
- 资助金额:
$ 5.94万 - 项目类别:
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