The Role of EpCAM Glycosylation in Breast Cancer Metastasis
EpCAM 糖基化在乳腺癌转移中的作用
基本信息
- 批准号:10605857
- 负责人:
- 金额:$ 5.27万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-05-01 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:AdhesionsAffectBasement membraneBiochemistryBiological AssayBiomedical EngineeringBlood VesselsBreastBreast Cancer CellBreast Cancer ModelBreast Cancer PatientBreast Cancer TreatmentBreast Cancer cell lineBreast Cancer therapyBreast cancer metastasisCRISPR/Cas technologyCancer BiologyCarcinomaCaringCell AdhesionCell Adhesion MoleculesCell LineCellsCellular biologyCessation of lifeColorectal CancerCommittee MembersComplementComplexCorrelation StudiesCycloheximideDNADataDevelopmentDigestionDiseaseDistantDistant MetastasisEducationEducational workshopEpithelial CellsFemaleGenerationsGlycobiologyGlycopeptidesGoalsGrowthHumanImmunologic Deficiency SyndromesImmunoprecipitationInvadedInvestmentsKnock-outLinkLiverLungMDA-MB-468Malignant NeoplasmsMalignant neoplasm of prostateMammary NeoplasmsMannoseMass Spectrum AnalysisMentorsMentorshipMetastatic Neoplasm to Lymph NodesMetastatic breast cancerMicroscopicMolecular BiologyMusMutateN-Glycosylation SiteNeoplasm MetastasisNoduleNormal tissue morphologyNude MicePathologistPatientsPatternPeptidesPhysiciansPolysaccharidesPost-Translational Protein ProcessingPre-Clinical ModelPrimary NeoplasmPropertyProteinsQuantitative Reverse Transcriptase PCRRoleSamplingScientistSiteSpectrometry, Mass, Matrix-Assisted Laser Desorption-IonizationSurvival RateTechniquesTestingTissuesTrainingTrypsinTumor TissueUnited StatesUniversitiesWidespread DiseaseWomanWorkWritingXenograft Modelcancer cellcareer developmentdoctoral studenteffective therapyexperienceexperimental studyglycosylationin vitro Assayin vivoinsightinterestknock-downliquid chromatography mass spectrometrylymph nodesmRNA Expressionmalignant breast neoplasmmammary epitheliummass spectrometric imagingmeetingsmembermigrationmouse modelmutantnano-liquid chromatographynew therapeutic targetnoveloverexpressionprogramsprotein expressionsuccesssymposiumtreatment strategytriple-negative invasive breast carcinomatumor growthtumor metabolismtumor xenograftundergraduate student
项目摘要
PROJECT SUMMARY
Breast cancer is a widespread disease that will claim the lives of over 40,000 US women in 2022 alone, with the
majority of these deaths resulting from stage IV disease, in which cancer has metastasized to distant regions,
as metastatic disease is difficult to treat and has few effective treatment options. Breast cancer cells metastasize
by invading the basement membrane, invading into blood vessels, circulating to distant tissues, leaving the blood
vessel, and colonizing that tissue. The epithelial cell adhesion molecule (EpCAM) plays a role in cell adhesion,
migration, and invasion, and has been linked to several epithelial cancers, including breast, prostate, and
colorectal cancer. Despite its potential to facilitate several steps of the metastatic cascade and its link to epithelial
cancers, the specific role of EpCAM in metastasis remains unknown. In his study of normal tissues, primary
tumors, and metastatic nodules of 17 metastatic breast cancer patients, our collaborator Dr. Pedram Argani
determined that EpCAM protein expression was increased in metastatic nodules, without a corresponding
increase in EpCAM mRNA expression. We therefore hypothesize that post-translational modification of EpCAM,
which has three known N-glycosylation sites and no known O-glycosylation sites, stabilizes and increases the
abundance of EpCAM in metastatic tissues. Our recent study of these same samples found that the abundance
of N-glycans was significantly increased in metastatic tissues versus primary tumors versus normal tissues and
identified 25 significantly differentially abundant N-glycans of interest. Our study also found that EpCAM protein
expression was significantly increased in metastatic tissues compared to primary tumors and was significantly
statistically correlated with the expression of seven N-glycans. Taken together, these data suggest that EpCAM
N-glycosylation may play a role in metastatic progression. The central hypothesis of this project is that increases
and changes in N-glycosylation stabilize EpCAM and allow it to facilitate metastasis. I propose to test this
hypothesis through the following specific aims: Aim 1: To elucidate the impact of EpCAM N-glycosylation on
EpCAM stability and adhesion in human breast cancer cells; Aim 2: To assess the impact of EpCAM N-
glycosylation on metastasis in mouse models of breast cancer. These aims will be achieved through a
combination of cancer biology, biochemistry, and mass spectrometry approaches in human triple-negative breast
cancer cell lines and breast cancer xenograft models. This work is significant because it will elucidate the role of
N-glycosylation of EpCAM in metastatic breast cancer, determine the specific N-glycosylation profile of EpCAM
in metastasizing breast cancer cells, and may subsequently uncover novel therapeutic targets and strategies in
metastatic breast cancer.
项目摘要
乳腺癌是一种广泛存在的疾病,仅在2022年就将夺去超过40,000名美国女性的生命,
这些死亡中的大多数是由IV期疾病引起的,其中癌症已经转移到遥远的地区,
因为转移性疾病很难治疗并且几乎没有有效的治疗选择。乳腺癌细胞转移
通过侵入基底膜,侵入血管,循环到远处的组织,
血管,并在该组织中定植。上皮细胞粘附分子(EpCAM)在细胞粘附中起作用,
迁移和侵袭,并与几种上皮癌有关,包括乳腺癌,前列腺癌,
结肠直肠癌尽管它有可能促进转移级联的几个步骤及其与上皮细胞的联系,
在癌症中,EpCAM在转移中的具体作用仍然未知。在他对正常组织的研究中,
肿瘤和转移性结节的17例转移性乳腺癌患者,我们的合作者Pedram Argani博士
确定EpCAM蛋白表达在转移性结节中增加,而没有相应的
EpCAM mRNA表达增加。因此,我们假设EpCAM的翻译后修饰,
其具有三个已知的N-糖基化位点而没有已知的O-糖基化位点,
转移组织中EpCAM的丰度。我们最近对这些样本的研究发现,
N-聚糖的浓度在转移性组织中显著增加,与原发性肿瘤相比,
鉴定了25种显著差异丰富的感兴趣的N-聚糖。我们的研究还发现EpCAM蛋白
与原发性肿瘤相比,转移性组织中的表达显著增加,
与七种N-聚糖的表达在统计学上相关。总之,这些数据表明EpCAM
N-糖基化可能在转移进展中起作用。该项目的核心假设是,
并且N-糖基化的变化稳定EpCAM并使其促进转移。我想测试一下
目的1:阐明EpCAM N-糖基化对细胞凋亡的影响。
EpCAM在人乳腺癌细胞中的稳定性和粘附性;目的2:评估EpCAM N-甲基化的影响。
在乳腺癌小鼠模型中,糖基化对转移的影响。这些目标将通过一个
癌症生物学、生物化学和质谱方法在人类三阴性乳腺癌中的组合
癌细胞系和乳腺癌异种移植模型。这项工作意义重大,因为它将阐明
转移性乳腺癌中EpCAM的N-糖基化,确定EpCAM的特异性N-糖基化谱
在转移性乳腺癌细胞中,并可能随后发现新的治疗靶点和策略,
转移性乳腺癌。
项目成果
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