Implantable pre-metastatic niche to elucidate the impact of chemotherapy-induced metastatic relapse
可植入的转移前生态位阐明化疗引起的转移复发的影响
基本信息
- 批准号:10362620
- 负责人:
- 金额:$ 35.18万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-03-11 至 2024-02-29
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAdjuvantAdjuvant TherapyAlgorithmsAnti-Inflammatory AgentsBiocompatible MaterialsBiomedical EngineeringBlood VesselsBone MarrowCancer BiologyCancer SurvivorCell CountCell physiologyCellsClinicalCrystallizationDataDevelopmentDichloromethylene DiphosphonateDoxorubicinEndothelial CellsEngraftmentEventEvolutionExperimental ModelsFVB MouseFemaleGoalsGrowthHepaticHumanImmuneImmunocompetentImplantIn SituIndividualInflammationInflammatoryInterdisciplinary StudyLiverLobeLongitudinal StudiesMeasuresMetastatic Neoplasm to the LiverModelingMolecularMonitorMouse Mammary Tumor VirusMusNeoplasm Circulating CellsNeoplasm MetastasisOpticsOrganPharmaceutical PreparationsPharmacologyPhasePhenotypePrimary NeoplasmPrognosisRegimenRegulationRelapseResearchResidual TumorsResourcesRiskSecondary toSeedsStandardizationStromal CellsTechniquesTherapeuticTimeTissue EngineeringTissue imagingTissuesTransgenic OrganismsTransplantationTumor Cell BiologyUncertaintyUnited StatesWorkanakinraanticancer researchbasebiomedical imagingchemotherapyeffectiveness evaluationepidemiologic dataepidemiology studyhydrogel scaffoldimaging modalityimmunoregulationimplant materialimprovedintravital imagingmacrophagemetastasis preventionmetastatic processmouse modelneoplastic cellnovelpatient subsetsporous hydrogelpreventquantitative imagingrecruitscaffoldstandard of caresubcutaneoustherapeutic targettooltumor
项目摘要
Epidemiological studies indicate that chemotherapy can increase the chance of metastasis in a subset patients,
but the underlying mechanism remains unclear because of a lack of relevant experimental models. The goal of
this proposal is to elucidate the impact of chemotherapy on metastatic relapse with a tissue-engineered
metastasis model that can capture metastatic niche evolution with a high level of molecular and cellular detail.
Inspired by the recent discovery of the pre-metastatic niche (PMN) in major metastatic organs, we have
developed a bone marrow stromal cell–seeded microfabricated porous hydrogel scaffold that creates a richly
vascularized proinflammatory microenvironment when it is subdermally implanted in a mouse. This implantable
PMN model has been shown to attract and support the engraftment and growth of circulating tumor cells and
can be serially implanted in syngeneic naive mice for long-term studies. The semitransparent materials of the
implant are compatible with quantitative imaging analysis via multiple imaging modalities including multiplex
immunohistostaining, CLARITY-based optical sectioning of entire scaffolds, and intravital imaging via a skinfold
window chamber.
Our central hypothesis is that tissue inflammation and remodeling induced by chemotherapy activates
dormant disseminated tumor cells and causes them to migrate and form in situ clusters as a function of cell
number. Forming clusters could allow the cells to overcome microenvironmental regulation and regain an
aggressive phenotype. We propose three specific aims: In Aim 1, we will generate subcutaneous and hepatic
PMN models in a MMTV-PyMT female mouse and demonstrate the long-term evolution of metastatic niche by
serially transplanting early metastatic niche established in primary mice to secondary syngeneic FVB mice. For
this purpose, we will generate MMTV-Luc2-PyMT mice that allow non-invasive long-term bioluminescent
monitoring of metastatic relapse. In Aim 2, we will use the techniques verified in Aim 1 to observe the effect of
chemotherapy with doxorubicin on the metastatic process in serially implanted bone marrow and liver PMN
models. In Aim 3, we will apply the established algorithm to measure potency to determine if adjuvant therapy
with anti-inflammatory (anakinra) or anti-macrophage (clodronate) drugs reduces doxorubicin-induced
metastatic relapse and will look at the effect of adjuvant timing. The proposed research is significant because it
has the potential to facilitate the development of better therapeutic regimens that can eliminate active residual
tumor cells without activating dormant disseminated tumor cells, and this would significantly improve long-term
metastasis prevention.
流行病学研究表明,化学疗法可以增加子群患者转移的机会,
但是,由于缺乏相关的实验模型,基本机制仍然不清楚。目标
该建议是阐明化学疗法对通过组织工程的转移缓解的影响
转移模型可以捕获具有高水平的分子和细胞细节的转移性利基进化。
受到最近在主要转移器官中发现的中转移利基(PMN)的启发,我们有
开发了一个基质细胞的骨髓 - 种子的微生物水凝胶A支架,可产生丰富的
血管促炎微环境将其下植入小鼠时。这个植入
已显示PMN模型吸引和支持循环肿瘤细胞的植入和生长
可以在合成的天真小鼠中串行植入长期研究。半透明的材料
植入物通过多种成像方式(包括多路复用)与定量成像分析兼容
免疫疗法,基于清晰的整个支架的光学切片,以及通过皮肤折叠的浸润成像
窗室。
我们的中心假设是,化学疗法诱导的组织炎症和重塑会激活
休眠的散布肿瘤细胞,并导致它们随着细胞的函数而迁移并形成原位簇
数字。形成簇可以使细胞克服微环境调节并持续存在
积极的表型。我们提出了三个具体目标:在AIM 1中,我们将产生皮下和肝
MMTV-PYMT雌鼠中的PMN模型,并证明了转移性生态位的长期演变
在初级小鼠中建立的辅助转移性壁裂的序列移植到继发性FVB小鼠中。为了
此目的,我们将生成MMTV-LUC2-PYMT小鼠,允许非侵入性长期生物发光
监测转移性缓解。在AIM 2中,我们将使用AIM 1中验证的技术来观察
阿霉素的化学疗法在连续植入的骨髓和肝PMN的转移过程中
型号。在AIM 3中,我们将应用已建立的算法来测量效力以确定是否辅助治疗
抗炎(Anakinra)或抗巨噬细胞(Clodronate)药物减少了阿霉素诱导的
转移性缓解,并将研究辅助时机的效果。拟议的研究很重要,因为它
有可能促进更好的治疗方案的发展,以消除主动残留
肿瘤细胞而不激活休眠的肿瘤细胞,这将显着改善长期
预防转移。
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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Jungwoo Lee其他文献
Jungwoo Lee的其他文献
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{{ truncateString('Jungwoo Lee', 18)}}的其他基金
Implantable pre-metastatic niche to elucidate the impact of chemotherapy-induced metastatic relapse
可植入的转移前生态位阐明化疗引起的转移复发的影响
- 批准号:
9891030 - 财政年份:2019
- 资助金额:
$ 35.18万 - 项目类别:
Implantable pre-metastatic niche to elucidate the impact of chemotherapy-induced metastatic relapse
可植入的转移前生态位阐明化疗引起的转移复发的影响
- 批准号:
10622445 - 财政年份:2019
- 资助金额:
$ 35.18万 - 项目类别:
Elucidating Essential Components of Bone Marrow Metastasis
阐明骨髓转移的重要组成部分
- 批准号:
8925016 - 财政年份:2014
- 资助金额:
$ 35.18万 - 项目类别:
Elucidating Essential Components of Bone Marrow Metastasis
阐明骨髓转移的重要组成部分
- 批准号:
8903811 - 财政年份:2014
- 资助金额:
$ 35.18万 - 项目类别:
Elucidating Essential Components of Bone Marrow Metastasis
阐明骨髓转移的重要组成部分
- 批准号:
9111859 - 财政年份:2014
- 资助金额:
$ 35.18万 - 项目类别:
Elucidating Essential Components of Bone Marrow Metastasis
阐明骨髓转移的重要组成部分
- 批准号:
8522170 - 财政年份:2012
- 资助金额:
$ 35.18万 - 项目类别:
Elucidating Essential Components of Bone Marrow Metastasis
阐明骨髓转移的重要组成部分
- 批准号:
8383166 - 财政年份:2012
- 资助金额:
$ 35.18万 - 项目类别:
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