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：
9973560
负责人：
Matthew D Ringel
金额：
$ 45.25万
依托单位：
OHIO STATE UNIVERSITY
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：
https://reporter.nih.gov/project-details/9973560
关键词：
Ablation Binding Biological Response Modifiers Calcineurin Cancer Cell Growth Cancer Etiology Cancer Model DNA Sequence Alteration Data Development Disease Disseminated Malignant Neoplasm Distant Distant Metastasis Environment Future Gatekeeping Gene Expression Genetic Engineering Genetically Engineered Mouse Genomics Growth Human Human Cell Line IL8 gene Immune Immune checkpoint inhibitor In Vitro Link Malignant Neoplasms Malignant neoplasm of thyroid Mediating Metastasis Suppression Microsatellite Instability Modeling Mus Neoplasm Metastasis Oncogenic PD-1/PD-L1 PTEN gene Papillary thyroid carcinoma Pathway interactions Patients Phenotype Play Process Proteins Regulation Reporting Role Signal Pathway Solid Neoplasm Testing Thyroid Gland Tissues Transcriptional Activation Tumor-infiltrating immune cells Xenograft procedure epigenetic regulation experimental study human tissue immune activation immunoregulation in vivo mRNA Expression mortality mouse model novel outcome forecast overexpression promoter protein expression protein function therapeutic target transcription factor tumor tumor progression tumorigenesis tumorigenic

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的癌症相关死亡率的直接原因。因此，确定晚期进展的守门人并定义其作用机理至关重要。甲状腺癌提供了一个出色的模型，可以鉴定由于其典型的长潜伏期和终阶段进展的速度迅速而导致晚期癌症进展的调节剂。我们的重点是将甲状腺癌远处转移性病变的独特基因组改变定义，并确定钙调蛋白1.4（RCAN1.4）的调节剂是一种新的转移抑制剂。此功能随后在其他实体瘤中报道。通过对人体组织的无偏基因组分析和验证性研究的结合，在人类细胞系，小鼠异种移植物和新开发的基因工程小鼠模型中的功能研究，我们已经确定了CAP-N-胶卷转录因子NFE2L3（NRF3）是由RCUN1.4损耗引起的重要下降功能调节器。此外，NFE2L3本身可以促进甲状腺癌细胞的生长和侵袭，并与预后不良有关。我们还表明，RCAN1.4损耗和NFE2L3的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中的允许的1型免疫环境有关，IL-8释放和基因表达由NFE2L3和NFE2L3的作用构成了IL8的启动器，该作用是IL-8的作用。调节甲状腺癌中的肿瘤免疫接口。尽管经常稳健的免疫细胞浸润，但进行性甲状腺癌通常与PD1/PDL1或微卫星不稳定性的过表达无关，因此检查点抑制剂在很大程度上效果不佳。这些数据突出了定义调节该肿瘤类型进展的免疫环境调节剂的重要性。总体假设是RCAN1.4损失和NFE2L3过表达诱导肿瘤性和促型免疫环境，促进甲状腺癌的进展。