Planar Cell Polarity Control in Melanoma Metastasis
黑色素瘤转移中的平面细胞极性控制
基本信息
- 批准号:10360007
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-04-01 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:AfghanistanAllelesBRAF geneBehaviorBlocking AntibodiesCancer PatientCell LineCell PolarityCell ProliferationCellsCessation of lifeChimera organismCleft PalateCyclin D1DefectDevelopmentDiagnosisDiseaseDisease OutcomeDistant MetastasisEctopic ExpressionExposure toFutureGelatinase AGenesGenetic studyGenomicsGoalsHealthcareHumanIn VitroIraqKnock-outLungLysosomesMEKsMalignant NeoplasmsMediatingMelaninsMelanoma CellMetastatic Neoplasm to the LungMilitary PersonnelMissionModelingMonitorMusNeoplasm MetastasisNeural Tube DefectsOrganPathway interactionsPatientsPharmaceutical PreparationsPlayPolycystic Kidney DiseasesProcessProteinsRas/RafRecurrenceResearchRoleSamplingSignal PathwaySkinSkin CancerSkin NeoplasmsSunlightSystemTechnologyTestingTherapeuticTissue MicroarrayTissuesTransgenic MiceTumor Cell MigrationUnited States Department of Veterans AffairsVeteransWorkbasecancer diagnosiscell killingcell motilityclinically relevantcongenital heart disorderdeafnessdrug developmentdrug discoveryepithelial to mesenchymal transitionexperimental studygain of functionhigh riskhuman diseasehuman tissuein vivoindexinginnovationinsightinterdisciplinary approachknock-downliquid crystal polymerlive cell imagingmelanocytemelanomamilitary veteranmouse modelmutantneoplasm registryneoplastic cellnovelnovel strategiesoverexpressionpatient derived xenograft modelplanar cell polaritypreventprogramsprospectiveprotein degradationsurvivorshiptranscriptomicsultraviolet
项目摘要
Melanoma is a highly aggressive cancer that begins in melanin-producing melanocytes in the skin. It accounts
for only about 1% of skin cancers, but it is the leading cause of skin cancer deaths. US military personnel have
higher rates of melanoma than civilians because of the heavy exposure to sunlight in the deployment setting.
Based on the Veterans Affairs Central Cancer Registry, melanoma is one of the five most frequently diagnosed
cancers among VA cancer patients. US Veterans will continue to be vulnerable to melanoma as the US military
currently is and has been recently engaged in missions in several high ultraviolet (UV) index zones, such as Iraq
and Afghanistan. Thus, there is a critical need to devise strategies to slow melanoma progression, leading to
extended or even permanent survivorship in Veteran patients. Current efforts in melanoma research are heavily
focused on blocking cell proliferation or killing tumor cells. However, it may also be possible to treat this disease
by preventing tumor cells from spreading to other organs. The planar cell polarity (PCP) pathway controls tissue
polarity during development by regulating the directional movement of cells and coordinating neighboring cells
to the tissue axes. Increasing evidence suggests that it also plays a role in cancer by promoting tumor cell
migration and invasion. Although some information is available regarding the PCP pathway in certain cancers,
its involvement in melanoma has not been studied. The long-term goal of our study is to dissect the role and
mechanism of the PCP pathway in melanoma development and progression. In our preliminary studies, we have
found that Frizzled 6 (FZD6), one of the core PCP genes, is overexpressed in multiple melanoma cell lines and
human tissues. Knockdown (KD) or knockout (KO) of FZD6 does not affect cell proliferation, but significantly
reduces the invasive ability of melanoma cells. In addition, we have found that KO of Fzd6 dramatically reduces
lung metastasis in the Pten/BRaf mouse model of melanoma. Therefore, we hypothesize that FZD6 promotes
melanoma invasion and metastasis by regulating cell polarity and could serve as a novel target for
melanoma management. We will test this hypothesis with the following three aims: (1) to determine the
mechanisms of FZD6 in promoting melanoma cell invasion in vitro; (2) to determine the functional significance
of FZD6 in melanoma metastasis in vivo; and (3) to determine the clinical relevance and therapeutic significance
of FZD6 in melanoma. The proposed research is innovative. We have assembled a team with diverse expertise
to take a multi-disciplinary approach using loss- and gain-of-function genetic studies, live-cell imaging, inducible
protein degradation, genomics, and drug discovery. The proposed research is significant. Our proposed aims
will not only unveil mechanistic insights into the FZD6-mediated PCP pathway in promoting melanoma
metastasis, but serve as proof-of-principle studies for drug development to target this system for melanoma
management. Since the Veteran population are at higher risk of developing malignant melanoma, our work is
relevant and significant to the health care of our Veterans.
黑色素瘤是一种高度侵袭性的癌症,始于皮肤中产生黑色素的黑素细胞。IT帐目
只有大约1%的皮肤癌患者,但它是皮肤癌死亡的主要原因。美国军事人员已经
由于在部署环境中大量暴露在阳光下,黑色素瘤的发病率比平民更高。
根据退伍军人事务中心癌症登记处的数据,黑色素瘤是最常见的五种诊断之一
VA癌症患者中的癌症。美国退伍军人将继续易患黑色素瘤
目前正在并最近一直在伊拉克等几个高紫外线指数区执行任务
还有阿富汗。因此,迫切需要制定策略来减缓黑色素瘤的进展,从而导致
延长甚至永久存活的退伍军人患者。目前在黑色素瘤研究方面的努力很大
专注于阻止细胞增殖或杀死肿瘤细胞。然而,也有可能治疗这种疾病。
通过防止肿瘤细胞扩散到其他器官。平面细胞极性(PCP)途径控制组织
通过调节细胞的定向运动和协调相邻细胞来调节发育过程中的极性
到组织轴上。越来越多的证据表明,它还通过促进肿瘤细胞在癌症中发挥作用。
移民和入侵。虽然关于某些癌症中的PCP途径有一些信息,
它与黑色素瘤的关系还没有研究过。我们研究的长期目标是剖析
PCP途径在黑色素瘤发生发展中的作用机制。在我们的初步研究中,我们有
发现核心PCP基因之一Frizzled6(FZD6)在多种黑色素瘤细胞系和
人体组织。FZD6基因敲除(KD)或敲除(KO)不影响细胞增殖,但显著
降低黑色素瘤细胞的侵袭能力。此外,我们还发现Fzd6的KO显著降低
PTEN/BRAF小鼠黑色素瘤模型的肺转移。因此,我们假设FZD6促进
黑色素瘤通过调节细胞极性侵袭和转移,可作为治疗的新靶点
黑色素瘤管理。我们将通过以下三个目标来检验这一假说:(1)确定
FZD6促进黑色素瘤细胞体外侵袭的机制;(2)确定其功能意义
FZD6在黑色素瘤体内转移中的作用;以及(3)确定其临床相关性和治疗意义
FZD6在黑色素瘤中的表达。提出的研究具有创新性。我们已经组建了一支拥有不同专业知识的团队
采用多学科方法,使用功能丧失和功能获得的遗传学研究,活细胞成像,诱导性
蛋白质降解、基因组学和药物发现。这项拟议的研究具有重要意义。我们提出的目标
不仅揭示了FZD6介导的PCP通路促进黑色素瘤的机制
转移,但作为针对黑色素瘤的药物开发的原则验证研究
管理层。由于退伍军人患恶性黑色素瘤的风险更高,我们的工作是
对我们退伍军人的医疗保健具有重要意义。
项目成果
期刊论文数量(0)
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Hao Chang其他文献
On the First Hochschild Cohomology of Cocommutative Hopf Algebras of Finite Representation Type
有限表示型共交换Hopf代数的第一Hochschild上同调
- DOI:
10.1093/qmathj/haaa020 - 发表时间:
2019-07 - 期刊:
- 影响因子:0
- 作者:
Hao Chang - 通讯作者:
Hao Chang
Hao Chang的其他文献
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{{ truncateString('Hao Chang', 18)}}的其他基金
Planar Cell Polarity Control in Melanoma Metastasis
黑色素瘤转移中的平面细胞极性控制
- 批准号:
10560473 - 财政年份:2022
- 资助金额:
-- - 项目类别:
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