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：
Matthew D Ringel
金额：
$ 44.34万
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/10400004
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 Prognosis 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 in vivo mRNA Expression mortality mouse model novel 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癌症相关死亡的直接原因。因此，识别晚期进展的看门人并定义其作用机制至关重要。甲状腺癌因其典型的长潜伏期和终末期进展速度快而提供了一个出色的模型来识别晚期癌症进展的调节因子。我们专注于定义甲状腺癌远处转移病灶的独特基因组改变，并确定钙调磷酸酶调节因子 1.4 (RCAN1.4) 作为一种新的转移抑制因子。随后在其他实体瘤中报道了这种功能。通过结合对人体组织的公正基因组分析和验证性研究，以及对人体细胞系、小鼠异种移植物和新开发的基因工程小鼠模型的功能研究，我们鉴定出了 Cap-N-Collar 转录因子 NFE2L3 (Nrf3)作为 RCAN1.4 缺失引起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功能，与不良预后相关。我们还表明，RCAN1.4 缺失和 NFE2L3 过表达与体外和体内免疫激活相关，NFE2L3 过表达与人甲状腺癌中允许的 1 型免疫环境相关，IL-8 释放和基因表达与受 NFE2L3 调节，并且 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机械作用。尽管免疫细胞浸润常常很强，但进展性甲状腺癌通常与 PD1/PDL1 过度表达或微卫星不稳定无关，因此，检查点抑制剂基本上无效。这些数据强调了定义调节这种肿瘤类型进展的免疫环境调节因子的重要性。总体假设是，RCAN1.4 缺失和 NFE2L3 过度表达会诱导致瘤和促转移的免疫环境，从而促进甲状腺癌的进展。