In vivo characterization of keratinocytes in the melanoma microenvironment
黑色素瘤微环境中角质形成细胞的体内表征
基本信息
- 批准号:10313790
- 负责人:
- 金额:$ 4.95万
- 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:2021-07-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AdhesionsAffectAnimal ModelBrain-Derived Neurotrophic FactorCellsClustered Regularly Interspaced Short Palindromic RepeatsDataDevelopmentElectroporationEndothelinGrowthGrowth FactorHistologyHumanImageIn VitroIndividualKnock-outLabelMelaninsMelanoma CellMelanosomesMethodsModelingMorphologyNeoplasm MetastasisParacrine CommunicationPatient-Focused OutcomesPhysical RestraintPhysiologyPigmentsPlayProliferatingProteinsQuantitative Reverse Transcriptase PCRRegulationResolutionRoleSkinSkin CancerStratum BasaleSystemTestingTissue SampleTissuesTransgenic OrganismsUp-RegulationWestern BlottingZebrafishbasecell motilitycell typeepithelial to mesenchymal transitionhuman tissuein vivoin vivo imaginginsightinterestkeratinocytemelanocytemelanomamembermigrationparacrineprogramspromoterrestrainttooltranscription factortranscriptometumortumor microenvironmenttumor progressiontumorigenic
项目摘要
PROJECT SUMMARY
Melanoma is the most lethal of skin cancers, with progression to local invasion and metastasis leading to poor
patient outcomes, highlighting the need for better understanding of melanoma progression. During melanoma
progression, tumorigenic cells must overcome growth restraints imposed by the microenvironmental
keratinocytes. Although much is known of keratinocyte regulatory controls on normal melanocytes, less is known
about their interactions in melanoma. Our preliminary data suggests that melanoma induces an epithelial-to-
mesenchymal transition (EMT) program in adjacent keratinocytes In Aim 1, I will investigate the role of
keratinocyte EMT on melanoma initiation. For this study, I will use the zebrafish as an animal model to study
in vivo interactions between keratinocytes and melanoma cells. I will induce spontaneous melanoma formation
in transgenic zebrafish lines with GFP labeled keratinocytes and use imaging to confirm morphological changes
indicative of EMT in tumor-associated keratinocytes (TAKs). Then, I will assess them for EMT transcription factor
and adhesion protein changes. We hypothesize that melanoma-induction of keratinocyte EMT will result in loss
of keratinocyte regulation on melanoma proliferation. We will test this hypothesis by knocking out EMT
transcription factors in keratinocytes and assess effects on melanoma initiation and proliferation in the zebrafish
model. In addition, our preliminary data has also highlighted an upregulation of paracrine signals from TAKs
involved in melanoma migration and invasion. In Aim 2, I will determine how keratinocyte-derived secreted
factors affect migration and invasion of nascent melanoma. To study migration of melanoma in vivo, I will
first optimize existing imaging pipelines in our lab to quantitatively to track cell migration by imaging of the
zebrafish skin. I can then assess the effect of knocking out keratinocyte-derived factors such as endothelin,
Wnt5A and BDNF using cell-type specific CRISPR-editing to determine their effects on migration. We
hypothesize that given the migratory role of these paracrine factors from in vitro data, we will see reduced
melanoma migration and invasion into adjacent tissues on migration tracking and histology by knocking-out these
factors in keratinocytes. By characterizing the role of tumor-associated keratinocytes in the melanoma
microenvironment, this proposal seeks to understand how melanoma modifies its microenvironment to overcome
its natural growth restraints and identify new targets to limit melanoma progression.
项目总结
黑色素瘤是最致命的皮肤癌,可进展为局部侵袭和转移。
患者的预后,突出了更好地了解黑色素瘤进展的必要性。在黑色素瘤期间
进展,致瘤细胞必须克服微环境施加的生长限制
角质形成细胞。尽管角质形成细胞对正常黑素细胞的调控已知很多,但知之甚少。
关于它们在黑色素瘤中的相互作用。我们的初步数据表明,黑色素瘤诱导上皮细胞到-
在目标1中,我将研究相邻角质形成细胞的间质转化(EMT)计划
角质形成细胞EMT在黑色素瘤发生中的作用。对于这项研究,我将使用斑马鱼作为动物模型来研究
角质形成细胞与黑色素瘤细胞的体内相互作用。我会诱发自发性黑色素瘤的形成
转基因斑马鱼中绿色荧光蛋白标记的角质形成细胞,并用成像证实形态变化
提示肿瘤相关角质形成细胞(TAK)中的EMT。然后,我会评估他们的EMT转录因子
黏附蛋白的变化。我们假设,黑色素瘤诱导的角质形成细胞EMT将导致丢失
角质形成细胞对黑色素瘤增殖的调控。我们将通过剔除EMT来检验这一假设
角质形成细胞中的转录因子及其对斑马鱼黑色素瘤启动和增殖的影响
模特。此外,我们的初步数据也强调了TAK旁分泌信号的上调
参与黑色素瘤的迁移和侵袭。在目标2中,我将确定角质形成细胞是如何分泌的
影响新生黑色素瘤迁移和侵袭的因素。为了研究黑色素瘤在体内的迁移,我将
首先优化我们实验室现有的成像管道,通过成像来定量跟踪细胞迁移
斑马鱼皮。然后我可以评估敲除角质形成细胞衍生因子的效果,如内皮素,
WNT5A和BDNF使用细胞类型特异性CRISPR编辑来确定它们对迁移的影响。我们
假设根据体外数据,考虑到这些旁分泌因子的迁移作用,我们将看到
敲除这些基因后黑色素瘤向邻近组织的迁移和侵袭对迁移跟踪和组织学的影响
角质形成细胞中的因子。通过表征肿瘤相关角质形成细胞在黑色素瘤中的作用
微环境,这项建议试图了解黑色素瘤是如何改变其微环境以克服
它的自然生长抑制,并确定新的目标,以限制黑色素瘤的进展。
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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Yilun Ma的其他文献
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{{ truncateString('Yilun Ma', 18)}}的其他基金
In vivo characterization of keratinocytes in the melanoma microenvironment
黑色素瘤微环境中角质形成细胞的体内表征
- 批准号:
10440282 - 财政年份:2021
- 资助金额:
$ 4.95万 - 项目类别:
In vivo characterization of keratinocytes in the melanoma microenvironment
黑色素瘤微环境中角质形成细胞的体内表征
- 批准号:
10643998 - 财政年份:2021
- 资助金额:
$ 4.95万 - 项目类别:
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