Characterization of ILEI/LIFR Axis-induced Intracellular Signaling
ILEI/LIFR 轴诱导的细胞内信号传导的表征
基本信息
- 批准号:10331812
- 负责人:
- 金额:$ 4.68万
- 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:2021-02-01 至 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:AKT2 geneAffectAttenuatedBindingBreast CarcinomaBreast Epithelial CellsCRISPR/Cas technologyCell Culture TechniquesCell MaintenanceCellsCharacteristicsClinicalConsensusDataDisease ProgressionElementsEpithelial CellsEventExposure toFatty acid glycerol estersGene ExpressionGene Expression ProfileGenesGenetic TranscriptionGoalsHeterogeneous-Nuclear RibonucleoproteinsHumanImmunodeficient MouseIn VitroInjectionsInterleukinsJAK2 geneKnock-outLaboratoriesLiteratureLuciferasesLungMaintenanceMammary NeoplasmsMammary glandMeasuresMediatingMetastatic Neoplasm to the LungMetastatic breast cancerModelingMusNeoplasm MetastasisNuclearParticipantPhenotypePhosphorylationPromoter RegionsPropertyProteinsPublishingRNA analysisReceptor SignalingRegulationRelapseResearchResidenciesResistanceRibonucleoproteinsRoleSTAT3 geneSignal PathwaySignal TransductionSite-Directed MutagenesisTailTherapeuticTransforming Growth Factor betaTranslatingTranslationsUp-RegulationVeinscancer stem cellchromatin immunoprecipitationepithelial to mesenchymal transitionexperimental studyin vivoknock-downleukemia inhibitory factor receptormalignant breast neoplasmmammarymammary epitheliumneoplastic cellnew therapeutic targetnovelpromoterprotein expressionreceptorreceptor expressionreceptor upregulationresponseself-renewalstem cell self renewalstem cellsstemnesstranscription factortranscriptome sequencingtranscriptomicstumortumor growthtumor progression
项目摘要
Project Summary
Our lab has previously identified a mechanism of transforming growth factor beta (TGFβ)-mediated
epithelial-to-mesenchymal transition (EMT) in murine mammary epithelium. We have shown that expression of
the interleukin-like EMT inducer (ILEI) protein is necessary to induce EMT in murine mammary gland cells
following exposure to TGFβ. ILEI has also been shown to increase the self-renewal capacity of epithelial cells
following EMT, through its interaction with leukemia inhibitory factor receptor (LIFR), suggesting that the
ILEI/LIFR signaling axis promotes breast cancer stem-cell (BCSC) phenotype. Further, our lab has shown that
TGFβ-induced upregulation of LIFR is ILEI-dependent. In cells derived from a mouse tumor progression model
created by our lab, spheroid formation capacity in non-adherent cell culture conditions is attenuated following
either ILEI or LIFR knockdown. Additionally, orthotopic grafts of cells with ILEI or LIFR knockdown display a
decrease in tumor growth and metastasis relative to control cells. We hypothesize that TGFβ-induced LIFR
regulation contributes to metastases.
The precise mechanisms of ILEI-mediated EMT and BCSC induction are unknown. Herein we aim to
interrogate ILEI/LIFR axis-mediated mechanisms downstream of TGFβ exposure that influence (1) the regulation
of LIFR protein expression and (2) the ensuing maintenance of self-renewal capacity and disease progression
in our model. In Specific Aim 1, the LIFR promoter sequence will be examined to identify key factors regulating
LIFR expression. In Specific Aim 2, transcriptomic data will be examined following ILEI/LIFR knockout to identify
a signature of ILEI/LIFR-regulated gene expression and its association with self-renewal capacity. In Specific
Aim 3, the role of LIFR will be examined in vivo to determine the impact of its expression upon outgrowth of
pulmonary tumors following tail vein injection of cells into immunodeficient mice.
Data from our experiments will characterize a signaling pathway associated with BCSC maintenance and
will potentially identify novel therapeutic targets. Our findings may translate to novel treatments for dormancy
and relapse in human metastatic breast cancer.
项目概要
我们的实验室之前已经确定了转化生长因子β(TGFβ)介导的机制
我们已经证明了小鼠乳腺上皮中上皮间质转化(EMT)的表达。
白细胞介素样 EMT 诱导蛋白 (ILEI) 是诱导小鼠乳腺细胞 EMT 所必需的
暴露于 TGFβ 后,ILEI 也被证明可以增加上皮细胞的自我更新能力。
EMT 后,通过其与白血病抑制因子受体 (LIFR) 的相互作用,表明
此外,我们的实验室还表明,ILEI/LIFR 信号轴可促进乳腺癌干细胞 (BCSC) 表型。
在源自小鼠肿瘤进展模型的细胞中,TGFβ 诱导的 LIFR 上调是 ILEI 依赖性的。
由我们的实验室创建,非贴壁细胞培养条件下的球体形成能力减弱如下
此外,ILEI 或 LIFR 敲低的细胞的原位移植物显示出
我们捕获了 TGFβ 诱导的 LIFR 相对于对照细胞的肿瘤生长和转移的减少。
调节有助于转移。
ILEI 介导的 EMT 和 BCSC 诱导的确切机制尚不清楚。
询问 TGFβ 暴露下游影响 (1) 调节的 ILEI/LIFR 轴介导机制
LIFR 蛋白表达以及 (2) 随后维持自我更新能力和疾病进展
在我们的模型中,将检查 LIFR 启动子序列以确定调节的关键因素。
在具体目标 2 中,将在 ILEI/LIFR 敲除后检查转录组数据以识别
ILEI/LIFR 调节的基因表达的特征及其与自我更新能力的关联。
目标 3,将在体内检查 LIFR 的作用,以确定其表达对细胞生长的影响
将细胞尾静脉注射到免疫缺陷小鼠体内后出现肺部肿瘤。
我们的实验数据将表征与 BCSC 维持和相关的信号通路
我们的发现可能会转化为新的休眠治疗方法。
和人类转移性乳腺癌的复发。
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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William Scott Streitfeld其他文献
William Scott Streitfeld的其他文献
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{{ truncateString('William Scott Streitfeld', 18)}}的其他基金
Characterization of ILEI/LIFR Axis-induced Intracellular Signaling
ILEI/LIFR 轴诱导的细胞内信号传导的表征
- 批准号:
10547814 - 财政年份:2021
- 资助金额:
$ 4.68万 - 项目类别:
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