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:9891030
- 负责人:
- 金额:$ 35.34万
- 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 MouseFemaleGoalsGrowthHepaticHumanHydrogelsImmuneImmunocompetentImplantIn SituIndividualInflammationInflammatoryInterdisciplinary StudyLiverLobeLongitudinal StudiesMeasuresMetastatic Neoplasm to the LiverModelingMolecularMonitorMouse Mammary Tumor VirusMusNeoplasm Circulating CellsNeoplasm MetastasisOpticsOrganPharmaceutical PreparationsPharmacologyPhasePhenotypePrimary NeoplasmRegimenRegulationRelapseResearchResidual TumorsResourcesRiskSecondary toSeedsStandardizationStromal CellsTechniquesTherapeuticTimeTissue EngineeringTissue imagingTissuesTransgenic OrganismsTransplantationTumor Cell BiologyUncertaintyUnited StatesWorkanakinraanticancer researchbasebioimagingchemotherapyeffectiveness evaluationepidemiologic dataepidemiology studyimaging modalityimmunoregulationimplant materialimprovedintravital imagingmacrophagemetastasis preventionmetastatic processmouse modelneoplastic cellnoveloutcome forecastpatient 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,化疗可以增加一部分患者的转移机会,
但由于缺乏相关的实验模型,其内在机制仍不清楚。
本研究旨在阐明化疗对组织工程肿瘤复发的影响,
转移模型,可以捕获具有高水平分子和细胞细节的转移小生境演变。
受最近在主要转移器官中发现的前转移小生境(PMN)的启发,我们
开发了一种骨髓基质细胞接种的微制造多孔水凝胶支架,
当其皮下植入小鼠体内时,其可促进血管化的促炎微环境。
PMN模型已显示吸引和支持循环肿瘤细胞的植入和生长,
可以连续植入同系幼稚小鼠进行长期研究。
植入物与通过多种成像模式进行定量成像分析相容
细胞染色,基于细胞学的整个支架的光学切片,以及通过皮褶的活体成像
窗口室。
我们的中心假设是化疗引起的组织炎症和重塑激活了
休眠的播散性肿瘤细胞,并导致它们迁移并作为细胞功能在原位形成簇
形成集群可以让细胞克服微环境调节,重新获得细胞的生长。
我们提出了三个具体的目标:在目标1中,我们将产生皮下和肝细胞,
在MMTV-BMPyMT雌性小鼠中建立PMN模型,并通过以下方法证明转移性小生境的长期演变:
将原代小鼠中建立的早期转移生态位连续移植到第二代同系FVB小鼠中。对于
为了达到这个目的,我们将产生MMTV-α-Luc 2-β-PyMT小鼠,其允许非侵入性的长期生物发光
在目标2中,我们将使用目标1中验证的技术来观察
阿霉素化疗对骨髓和肝脏中性粒细胞转移过程的影响
在目标3中,我们将应用已建立的算法来测量效力,以确定辅助治疗是否
与抗炎(阿那白滞素)或抗巨噬细胞(氯膦酸盐)药物联合使用,
转移复发,并将着眼于辅助时机的影响。拟议的研究是重要的,因为它
有可能促进开发更好的治疗方案,
肿瘤细胞,而不激活休眠的播散性肿瘤细胞,这将显着改善长期生存
转移预防。
项目成果
期刊论文数量(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:
10362620 - 财政年份:2019
- 资助金额:
$ 35.34万 - 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:
$ 35.34万 - 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:
$ 35.34万 - 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:
$ 35.34万 - 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:
$ 35.34万 - 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:
$ 35.34万 - 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:
$ 35.34万 - 项目类别:
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