RCAN 1.4 metastasis suppressor in thyroid cancer
RCAN 1.4 甲状腺癌转移抑制因子
基本信息
- 批准号:10400004
- 负责人:
- 金额:$ 44.34万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AblationBindingBiological Response ModifiersCalcineurinCancer Cell GrowthCancer EtiologyCancer ModelDNA Sequence AlterationDataDevelopmentDiseaseDisseminated Malignant NeoplasmDistantDistant MetastasisEnvironmentFutureGatekeepingGene ExpressionGenetic EngineeringGenetically Engineered MouseGenomicsGrowthHumanHuman Cell LineIL8 geneImmuneImmune checkpoint inhibitorIn VitroLinkMalignant NeoplasmsMalignant neoplasm of thyroidMediatingMetastasis SuppressionMicrosatellite InstabilityModelingMusNeoplasm MetastasisOncogenicPD-1/PD-L1PTEN genePapillary thyroid carcinomaPathway interactionsPatientsPhenotypePlayProcessPrognosisProteinsRegulationReportingRoleSignal PathwaySolid NeoplasmTestingThyroid GlandTissuesTranscriptional ActivationTumor-infiltrating immune cellsXenograft procedureepigenetic regulationexperimental studyhuman tissueimmune activationin vivomRNA Expressionmortalitymouse modelnoveloverexpressionpromoterprotein expressionprotein functiontherapeutic targettranscription factortumortumor progressiontumorigenesistumorigenic
项目摘要
Progressive metastasis is the proximate cause of cancer-related mortality for the majority of patients with solid tumors. Identifying gatekeepers of late stage progression and defining their mechanisms of action is therefore crucial. Thyroid cancer provides an outstanding model to identify regulators of late stage cancer progression due to its typical long latency and the often rapid pace of end-stage progression. We have focused on defining unique genomic alterations in distant metastatic lesions in thyroid cancer and identified Regulator of Calcineurin 1.4 (RCAN1.4) as a new metastasis suppressor. This function has subsequently been reported in other solid tumors. Through a combination of unbiased genomic analysis and confirmatory studies of human tissues, and functional studies in human cell lines, mouse xenografts, and newly-developed genetically engineered mouse models, we have identified the Cap-N-Collar transcription factor, NFE2L3 (Nrf3) as a critical downstream functional regulator induced by RCAN1.4 loss. In addition, NFE2L3 itself functions to promote thyroid cancer cell growth and invasion and is associated with poor prognosis. We also have shown that RCAN1.4 loss and NFE2L3 overexpression are associated with immune activation in vitro and in vivo, that overexpression of NFE2L3 is associated with a permissive type 1 immune environment in human thyroid cancer, that IL-8 release and gene expression are regulated by NFE2L3, and that NFE2L3 directly binds to the IL8 promoter and regulates its activity, suggesting a mechanistic role in regulation the tumor-immune interface in thyroid cancer. Progressive thyroid cancers are typically not associated with overexpression of PD1/PDL1 or microsatellite instability, despite often robust immune cell infiltrate, thus, checkpoint inhibitors have been largely ineffective. These data highlight the importance of defining regulators of the immune environment that regulate progression of this tumor type. The overall hypothesis is that RCAN1.4 loss and NFE2L3 overexpression induce a tumorigenic and pro-metastatic immune environment that facilitates thyroid cancer progression.
进行性转移是大多数实体瘤患者癌症相关死亡的直接原因。因此,确定后期进展的把关人并确定其行动机制至关重要。甲状腺癌由于其典型的长潜伏期和通常较快的终末期进展速度,为识别晚期癌症进展的调节因素提供了一个杰出的模型。我们专注于确定甲状腺癌远处转移灶中独特的基因组改变,并确定钙调神经磷酸酶1.4(RCAN1.4)调节因子是一种新的转移抑制因子。这一功能随后在其他实体肿瘤中也有报道。通过对人类组织的无偏倚基因组分析和验证性研究,以及对人类细胞系、小鼠异种移植和新开发的基因工程小鼠模型的功能研究,我们已经确定Cap-N-COLLAR转录因子NFE2L3(Nrf3)是RCAN1.4缺失诱导的关键下游功能调节因子。此外,NFE2L3本身具有促进甲状腺癌细胞生长和侵袭的作用,并与预后不良有关。我们还发现,RCAN1.4缺失和NFE2L3过表达与体外和体内的免疫激活有关,NFE2L3的过表达与人类甲状腺癌的1型免疫环境有关,IL-8的释放和基因表达受NFE2L3的调节,NFE2L3直接与IL8启动子结合并调节其活性,这表明NFE2L3在调节甲状腺癌的肿瘤-免疫界面中发挥了机械作用。进展性甲状腺癌通常与PD1/PDL1的过度表达或微卫星不稳定无关,尽管通常有强大的免疫细胞渗透,因此检查点抑制剂在很大程度上是无效的。这些数据强调了确定免疫环境调节器的重要性,免疫环境调节器调节这种类型的肿瘤的进展。总体假设是RCAN1.4缺失和NFE2L3过表达诱导了促肿瘤和促转移的免疫环境,促进了甲状腺癌的进展。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Matthew D Ringel其他文献
Matthew D Ringel的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Matthew D Ringel', 18)}}的其他基金
RCAN 1.4 metastasis suppressor in thyroid cancer
RCAN 1.4 甲状腺癌转移抑制因子
- 批准号:
9973560 - 财政年份:2020
- 资助金额:
$ 44.34万 - 项目类别:
RCAN 1.4 metastasis suppressor in thyroid cancer
RCAN 1.4 甲状腺癌转移抑制因子
- 批准号:
10604328 - 财政年份:2020
- 资助金额:
$ 44.34万 - 项目类别:
Role of p21-activated kinases in thyroid cancer
p21 激活激酶在甲状腺癌中的作用
- 批准号:
10377551 - 财政年份:2018
- 资助金额:
$ 44.34万 - 项目类别:
The OSU Center for Clinical and Translational Science: Advancing Today's Discoveries to Improve Health
俄勒冈州立大学临床和转化科学中心:推进当今的发现以改善健康
- 批准号:
10414809 - 财政年份:2018
- 资助金额:
$ 44.34万 - 项目类别:
The Ohio State University and MD Anderson Cancer Center Thyroid Cancer SPORE
俄亥俄州立大学和 MD 安德森癌症中心甲状腺癌孢子
- 批准号:
8741949 - 财政年份:2013
- 资助金额:
$ 44.34万 - 项目类别:
Developing Combination Therapies for Medullary Thyroid Cancer
开发甲状腺髓样癌的联合疗法
- 批准号:
8588547 - 财政年份:2013
- 资助金额:
$ 44.34万 - 项目类别:
The Ohio State University and MD Anderson Cancer Center Thyroid Cancer SPORE
俄亥俄州立大学和 MD 安德森癌症中心甲状腺癌孢子
- 批准号:
8548721 - 财政年份:2013
- 资助金额:
$ 44.34万 - 项目类别:
Integrated Clinicopathology and Biorespository Core
综合临床病理学和生物仓库核心
- 批准号:
8588551 - 财政年份:2013
- 资助金额:
$ 44.34万 - 项目类别:
相似国自然基金
帽结合蛋白(cap binding protein)调控乙烯信号转导的分子机制
- 批准号:32170319
- 批准年份:2021
- 资助金额:58.00 万元
- 项目类别:面上项目
帽结合蛋白(cap binding protein)调控乙烯信号转导的分子机制
- 批准号:
- 批准年份:2021
- 资助金额:58 万元
- 项目类别:
ID1 (Inhibitor of DNA binding 1) 在口蹄疫病毒感染中作用机制的研究
- 批准号:31672538
- 批准年份:2016
- 资助金额:62.0 万元
- 项目类别:面上项目
番茄EIN3-binding F-box蛋白2超表达诱导单性结实和果实成熟异常的机制研究
- 批准号:31372080
- 批准年份:2013
- 资助金额:80.0 万元
- 项目类别:面上项目
P53 binding protein 1 调控乳腺癌进展转移及化疗敏感性的机制研究
- 批准号:81172529
- 批准年份:2011
- 资助金额:58.0 万元
- 项目类别:面上项目
DBP(Vitamin D Binding Protein)在多发性硬化中的作用和相关机制的蛋白质组学研究
- 批准号:81070952
- 批准年份:2010
- 资助金额:35.0 万元
- 项目类别:面上项目
研究EB1(End-Binding protein 1)的癌基因特性及作用机制
- 批准号:30672361
- 批准年份:2006
- 资助金额:24.0 万元
- 项目类别:面上项目
相似海外基金
Collaborative Research: NSF-BSF: How cell adhesion molecules control neuronal circuit wiring: Binding affinities, binding availability and sub-cellular localization
合作研究:NSF-BSF:细胞粘附分子如何控制神经元电路布线:结合亲和力、结合可用性和亚细胞定位
- 批准号:
2321481 - 财政年份:2024
- 资助金额:
$ 44.34万 - 项目类别:
Continuing Grant
Collaborative Research: NSF-BSF: How cell adhesion molecules control neuronal circuit wiring: Binding affinities, binding availability and sub-cellular localization
合作研究:NSF-BSF:细胞粘附分子如何控制神经元电路布线:结合亲和力、结合可用性和亚细胞定位
- 批准号:
2321480 - 财政年份:2024
- 资助金额:
$ 44.34万 - 项目类别:
Continuing Grant
Alkane transformations through binding to metals
通过与金属结合进行烷烃转化
- 批准号:
DP240103289 - 财政年份:2024
- 资助金额:
$ 44.34万 - 项目类别:
Discovery Projects
NPBactID - Differential binding of peptoid functionalized nanoparticles to bacteria for identifying specific strains
NPBactID - 类肽功能化纳米粒子与细菌的差异结合,用于识别特定菌株
- 批准号:
EP/Y029542/1 - 财政年份:2024
- 资助金额:
$ 44.34万 - 项目类别:
Fellowship
Conformations of musk odorants and their binding to human musk receptors
麝香气味剂的构象及其与人类麝香受体的结合
- 批准号:
EP/X039420/1 - 财政年份:2024
- 资助金额:
$ 44.34万 - 项目类别:
Research Grant
Postdoctoral Fellowship: OPP-PRF: Understanding the Role of Specific Iron-binding Organic Ligands in Governing Iron Biogeochemistry in the Southern Ocean
博士后奖学金:OPP-PRF:了解特定铁结合有机配体在控制南大洋铁生物地球化学中的作用
- 批准号:
2317664 - 财政年份:2024
- 资助金额:
$ 44.34万 - 项目类别:
Standard Grant
I-Corps: Translation Potential of Real-time, Ultrasensitive Electrical Transduction of Biological Binding Events for Pathogen and Disease Detection
I-Corps:生物结合事件的实时、超灵敏电转导在病原体和疾病检测中的转化潜力
- 批准号:
2419915 - 财政年份:2024
- 资助金额:
$ 44.34万 - 项目类别:
Standard Grant
The roles of a universally conserved DNA-and RNA-binding domain in controlling MRSA virulence and antibiotic resistance
普遍保守的 DNA 和 RNA 结合域在控制 MRSA 毒力和抗生素耐药性中的作用
- 批准号:
MR/Y013131/1 - 财政年份:2024
- 资助金额:
$ 44.34万 - 项目类别:
Research Grant
CRII: OAC: Development of a modular framework for the modeling of peptide and protein binding to membranes
CRII:OAC:开发用于模拟肽和蛋白质与膜结合的模块化框架
- 批准号:
2347997 - 财政年份:2024
- 资助金额:
$ 44.34万 - 项目类别:
Standard Grant
How lipid binding proteins shape the activity of nuclear hormone receptors
脂质结合蛋白如何影响核激素受体的活性
- 批准号:
DP240103141 - 财政年份:2024
- 资助金额:
$ 44.34万 - 项目类别:
Discovery Projects