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色素细胞。这账户
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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